ABCMdb

ABCC11 p.Gly180Arg

Predicted by SNAP2:	A: D (85%), C: D (95%), D: D (91%), E: D (95%), F: D (91%), H: D (91%), I: D (91%), K: D (91%), L: D (91%), M: D (91%), N: D (95%), P: D (95%), Q: D (85%), R: D (66%), S: D (75%), T: D (85%), V: D (91%), W: D (95%), Y: D (91%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D,

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[hide] Ubiquitin-mediated proteasomal degradation of ABC ... J Pharm Sci. 2011 Sep;100(9):3602-19. doi: 10.1002/jps.22615. Epub 2011 May 12. Nakagawa H, Toyoda Y, Wakabayashi-Nakao K, Tamaki H, Osumi M, Ishikawa T
Ubiquitin-mediated proteasomal degradation of ABC transporters: a new aspect of genetic polymorphisms and clinical impacts.
J Pharm Sci. 2011 Sep;100(9):3602-19. doi: 10.1002/jps.22615. Epub 2011 May 12., [PMID:21567408]

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The interindividual variation in the rate of drug metabolism and disposition has been known for many years. Pharmacogenomics dealing with heredity and response to drugs is a part of science that attempts to explain variability of drug responses and to search for the genetic basis of such variations or differences. Genetic polymorphisms of drug metabolizing enzymes and drug transporters have been found to play a significant role in the patients' responses to medication. Accumulating evidence demonstrates that certain nonsynonymous polymorphisms have great impacts on the protein stability and degradation, as well as the function of drug metabolizing enzymes and transporters. The aim of this review article is to address a new aspect of protein quality control in the endoplasmic reticulum and to present examples regarding the impact of nonsynonymous single-nucleotide polymorphisms on the protein stability of thiopurine S-methyltransferase as well as ATP-binding cassette (ABC) transporters including ABCC4, cystic fibrosis transmembrane conductance regulator (CFTR, ABCC7), ABCC11, and ABCG2. Furthermore, we will discuss the molecular mechanisms underlying posttranslational modifications (intramolecular and intermolecular disulfide bond formation and N-linked glycosylation) and ubiquitin-mediated proteasomal degradation of ABCG2, one of the major drug transporter proteins in humans.

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49 Among them, the SNP 538G>A has been found to greatly affect the function and stability of de novo synthesized ABCC11 protein.50 The SNP 538G>A causes amino acid substitution at 180 (Gly180Arg) in the first transmembrane helix (TM1) and impairs N-linked glycosylation of the de novo synthesized ABCC11 protein. Login to comment

[hide] Multidrug resistance proteins (MRPs, ABCCs): impor... Handb Exp Pharmacol. 2011;(201):299-323. Keppler D
Multidrug resistance proteins (MRPs, ABCCs): importance for pathophysiology and drug therapy.
Handb Exp Pharmacol. 2011;(201):299-323., [PMID:21103974]

Abstract [show]
The nine multidrug resistance proteins (MRPs) represent the major part of the 12 members of the MRP/CFTR subfamily belonging to the 48 human ATP-binding cassette (ABC) transporters. Cloning, functional characterization, and cellular localization of most MRP subfamily members have identified them as ATP-dependent efflux pumps with a broad substrate specificity for the transport of endogenous and xenobiotic anionic substances localized in cellular plasma membranes. Prototypic substrates include glutathione conjugates such as leukotriene C(4) for MRP1, MRP2, and MRP4, bilirubin glucuronosides for MRP2 and MRP3, and cyclic AMP and cyclic GMP for MRP4, MRP5, and MRP8. Reduced glutathione (GSH), present in living cells at millimolar concentrations, modifies the substrate specificities of several MRPs, as exemplified by the cotransport of vincristine with GSH by MRP1, or by the cotransport of GSH with bile acids or of GSH with leukotriene B(4) by MRP4.The role of MRP subfamily members in pathophysiology may be illustrated by the MRP-mediated release of proinflammatory and immunomodulatory mediators such as leukotrienes and prostanoids. Pathophysiological consequences of many genetic variants leading to a lack of functional MRP protein in the plasma membrane are observed in the hereditary MRP2 deficiency associated with conjugated hyperbilirubinemia in Dubin-Johnson syndrome, in pseudoxanthoma elasticum due to mutations in the MRP6 (ABCC6) gene, or in the type of human earwax and osmidrosis determined by single nucleotide polymorphisms in the MRP8 (ABCC8) gene. The hepatobiliary and renal elimination of many drugs and their metabolites is mediated by MRP2 in the hepatocyte canalicular membrane and by MRP4 as well as MRP2 in the luminal membrane of kidney proximal tubules. Therefore, inhibition of these efflux pumps affects pharmacokinetics, unless compensated by other ATP-dependent efflux pumps with overlapping substrate specificities.

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265 The single-nucleotide polymorphism 538G>A in the ABCC11 gene, corresponding to the Gly180Arg variant in human MRP8, determines the earwax type (Yoshiura et al. 2006; Toyoda et al. 2009) and prevents the secretion of amino acid conjugates determining human axillary odor (Martin et al. 2010). Login to comment
267 The Gly180Arg variant lacks N-linked glycosylation and is recognized as a misfolded protein undergoing proteasomal degradation (Toyoda et al. 2009). Login to comment

[hide] Xenobiotic, bile acid, and cholesterol transporter... Pharmacol Rev. 2010 Mar;62(1):1-96. Epub 2010 Jan 26. Klaassen CD, Aleksunes LM
Xenobiotic, bile acid, and cholesterol transporters: function and regulation.
Pharmacol Rev. 2010 Mar;62(1):1-96. Epub 2010 Jan 26., [PMID:20103563]

Abstract [show]
Transporters influence the disposition of chemicals within the body by participating in absorption, distribution, and elimination. Transporters of the solute carrier family (SLC) comprise a variety of proteins, including organic cation transporters (OCT) 1 to 3, organic cation/carnitine transporters (OCTN) 1 to 3, organic anion transporters (OAT) 1 to 7, various organic anion transporting polypeptide isoforms, sodium taurocholate cotransporting polypeptide, apical sodium-dependent bile acid transporter, peptide transporters (PEPT) 1 and 2, concentrative nucleoside transporters (CNT) 1 to 3, equilibrative nucleoside transporter (ENT) 1 to 3, and multidrug and toxin extrusion transporters (MATE) 1 and 2, which mediate the uptake (except MATEs) of organic anions and cations as well as peptides and nucleosides. Efflux transporters of the ATP-binding cassette superfamily, such as ATP-binding cassette transporter A1 (ABCA1), multidrug resistance proteins (MDR) 1 and 2, bile salt export pump, multidrug resistance-associated proteins (MRP) 1 to 9, breast cancer resistance protein, and ATP-binding cassette subfamily G members 5 and 8, are responsible for the unidirectional export of endogenous and exogenous substances. Other efflux transporters [ATPase copper-transporting beta polypeptide (ATP7B) and ATPase class I type 8B member 1 (ATP8B1) as well as organic solute transporters (OST) alpha and beta] also play major roles in the transport of some endogenous chemicals across biological membranes. This review article provides a comprehensive overview of these transporters (both rodent and human) with regard to tissue distribution, subcellular localization, and substrate preferences. Because uptake and efflux transporters are expressed in multiple cell types, the roles of transporters in a variety of tissues, including the liver, kidneys, intestine, brain, heart, placenta, mammary glands, immune cells, and testes are discussed. Attention is also placed upon a variety of regulatory factors that influence transporter expression and function, including transcriptional activation and post-translational modifications as well as subcellular trafficking. Sex differences, ontogeny, and pharmacological and toxicological regulation of transporters are also addressed. Transporters are important transmembrane proteins that mediate the cellular entry and exit of a wide range of substrates throughout the body and thereby play important roles in human physiology, pharmacology, pathology, and toxicology.

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6947 It is noteworthy that dry earwax has been linked to a polymorphism (G180R) in ABCC11 (MRP8) that is more prevalent in persons of Chinese and Korean descent (Yoshiura et al., 2006; Kitano et al., 2008). Login to comment
6949 Subsequently, the G180R variant in ABCC11 was associated with not only dry earwax but also lower colostrum production in Japanese women (Miura et al., 2007). Login to comment
6944 It is noteworthy that dry earwax has been linked to a polymorphism (G180R) in ABCC11 (MRP8) that is more prevalent in persons of Chinese and Korean descent (Yoshiura et al., 2006; Kitano et al., 2008). Login to comment
6946 Subsequently, the G180R variant in ABCC11 was associated with not only dry earwax but also lower colostrum production in Japanese women (Miura et al., 2007). Login to comment

[hide] Recent advances in pharmacogenomics of ABC transpo... Pharmacogenomics. 2012 Apr;13(6):633-6. Ishikawa T
Recent advances in pharmacogenomics of ABC transporters involved in breast cancer therapy.
Pharmacogenomics. 2012 Apr;13(6):633-6., [PMID:22515603]

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62 On the other hand, one nonsynonymous SNP, 538G>A (Gly180Arg), in the ABCC11 gene greatly affects the function and stability of the de novo synthesized variant protein. The SNP (Arg180) variant is recognized as a misfolded protein in the endoplasmic reticulum and readily undergoes proteasomal degradation. Login to comment
138 21 Lang T, Justenhoven C, Winter S et al. The earwax-associated SNP c.538G>A (G180R) in ABCC11 is not associated with breast cancer risk in Europeans. Login to comment

[hide] Multidrug resistance proteins (MRPs/ABCCs) in canc... FEBS J. 2011 Sep;278(18):3226-45. doi: 10.1111/j.1742-4658.2011.08235.x. Epub 2011 Aug 1. Chen ZS, Tiwari AK
Multidrug resistance proteins (MRPs/ABCCs) in cancer chemotherapy and genetic diseases.
FEBS J. 2011 Sep;278(18):3226-45. doi: 10.1111/j.1742-4658.2011.08235.x. Epub 2011 Aug 1., [PMID:21740521]

Abstract [show]
The ATP-binding cassette (ABC) transporters are a superfamily of membrane proteins that are best known for their ability to transport a wide variety of exogenous and endogenous substances across membranes against a concentration gradient via ATP hydrolysis. There are seven subfamilies of human ABC transporters, one of the largest being the 'C' subfamily (gene symbol ABCC). Nine ABCC subfamily members, the so-called multidrug resistance proteins (MRPs) 1-9, have been implicated in mediating multidrug resistance in tumor cells to varying degrees as the efflux extrude chemotherapeutic compounds (or their metabolites) from malignant cells. Some of the MRPs are also known to either influence drug disposition in normal tissues or modulate the elimination of drugs (or their metabolites) via hepatobiliary or renal excretory pathways. In addition, the cellular efflux of physiologically important organic anions such as leukotriene C(4) and cAMP is mediated by one or more of the MRPs. Finally, mutations in several MRPs are associated with human genetic disorders. In this minireview, the current biochemical and physiological knowledge of MRP1-MRP9 in cancer chemotherapy and human genetic disease is summarized. The mutations in MRP2/ABCC2 leading to conjugated hyperbilirubinemia (Dubin-Johnson syndrome) and in MRP6/ABCC6 leading to the connective tissue disorder Pseudoxanthoma elasticum are also discussed.

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242 MRP8 / ABCC11 and dry /wet ear wax Insight into a physiological role for MRP8 in cerumen (ear wax) secretion by the ceruminous apocrine glands was revealed by the identification of a single nucleotide polymorphism, 538G>A (Gly180Arg) in the MRP8 gene, which was associated with the production of wet rather than dry ear wax [184]. Login to comment
248 In membrane vesicles studies, the G180R mutant of MRP8 was unable to transport cAMP, again supporting the notion that a deficiency of MRP8 transport activity is responsible for the dry ear wax type. Login to comment

[hide] The earwax-associated SNP c.538G>A (G180R) in ABCC... Breast Cancer Res Treat. 2011 Oct;129(3):993-9. Epub 2011 Jun 8. Lang T, Justenhoven C, Winter S, Baisch C, Hamann U, Harth V, Ko YD, Rabstein S, Spickenheuer A, Pesch B, Bruning T, Schwab M, Brauch H
The earwax-associated SNP c.538G>A (G180R) in ABCC11 is not associated with breast cancer risk in Europeans.
Breast Cancer Res Treat. 2011 Oct;129(3):993-9. Epub 2011 Jun 8., [PMID:21655989]

Abstract [show]
Genetic polymorphisms of human ABC-transporter genes have been suggested to modulate breast cancer risk in the general population. In particular ABCC11 (MRP8), which is highly expressed in breast cancer tissue and involved in the efflux of conjugated estrogen metabolites such as estrone-3-sulfate and estradiol-17beta-glucuronide, has recently been proposed as a potential risk factor for female breast cancer. The wet earwax-associated G-allele of the c.538G>A polymorphism was associated with an increased risk for breast cancer in Japanese women. In contrast, no evidence for such an association could be observed in Caucasian women. We aimed to confirm/refute the association of the c.538G>A variant in ABCC11 with breast cancer risk and/or histo-pathological tumor characteristics in an independent population-based breast cancer case-control study from Germany comprising 1021 cases and 1015 age-matched controls. No association for allele and genotype frequencies of the 538G>A variant in ABCB11 with breast cancer risk was found. Our data suggest that the c.538G>A variation in ABCC11 does not contribute to breast carcinogenesis in women of European descent.

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0 BRIEF REPORT The earwax-associated SNP c.538G>A (G180R) in ABCC11 is not associated with breast cancer risk in Europeans Thomas Lang • Christina Justenhoven • Stefan Winter • Christian Baisch • Ute Hamann • Volker Harth • Yon-Dschun Ko • Sylvia Rabstein • Anne Spickenheuer • Beate Pesch • Thomas Bru¨ning • Matthias Schwab • Hiltrud Brauch Received: 23 May 2011 / Accepted: 24 May 2011 / Published online: 8 June 2011 Ó Springer Science+Business Media, LLC. 2011 Abstract Genetic polymorphisms of human ABC-transporter genes have been suggested to modulate breast cancer risk in the general population. Login to comment
16 A loss-of-function and nonsynonymous SNP (c.538G[A; rs17822931) encoding the amino acid substitution G180R of ABCC11 recently has been shown to underlie the formation of cerumen, i.e. either wet or dry earwax. Login to comment

[hide] No evidence for an association between the earwax-... Breast Cancer Res Treat. 2011 Feb;126(1):235-9. Epub 2010 Dec 17. Beesley J, Johnatty SE, Chen X, Spurdle AB, Peterlongo P, Barile M, Pensotti V, Manoukian S, Radice P, Chenevix-Trench G
No evidence for an association between the earwax-associated polymorphism in ABCC11 and breast cancer risk in Caucasian women.
Breast Cancer Res Treat. 2011 Feb;126(1):235-9. Epub 2010 Dec 17., [PMID:21165769]

Abstract [show]
ABCC11 is an ATP-binding cassette transporter responsible for the transport of a diverse range of lipophilic compounds. A single nucleotide polymorphism (SNP) encoding an amino acid change has recently been shown to determine whether cerumen (earwax) is wet or dry. We hypothesised that this ABCC11 SNP may be associated with breast cancer risk because an association has been reported between wet earwax and increased risk of breast cancer. We therefore analysed the frequency of the functional SNP in 1342 cases and 2256 controls from two breast cancer studies of Caucasian women but found no evidence for an association with breast cancer risk.

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9 A non-synonymous coding SNP (c.538G[A; rs17822931) encoding amino acid substitution Gly180Arg of ABCC11 has recently been shown to underlie the formation of either wet or dry cerumen (earwax) [5]. Login to comment

[hide] The impact of natural selection on an ABCC11 SNP d... Mol Biol Evol. 2011 Jan;28(1):849-57. Epub 2010 Oct 11. Ohashi J, Naka I, Tsuchiya N
The impact of natural selection on an ABCC11 SNP determining earwax type.
Mol Biol Evol. 2011 Jan;28(1):849-57. Epub 2010 Oct 11., [PMID:20937735]

Abstract [show]
A nonsynonymous single nucleotide polymorphism (SNP), rs17822931-G/A (538G>A; Gly180Arg), in the ABCC11 gene determines human earwax type (i.e., wet or dry) and is one of most differentiated nonsynonymous SNPs between East Asian and African populations. A recent genome-wide scan for positive selection revealed that a genomic region spanning ABCC11, LONP2, and SIAH1 genes has been subjected to a selective sweep in East Asians. Considering the potential functional significance as well as the population differentiation of SNPs located in that region, rs17822931 is the most plausible candidate polymorphism to have undergone geographically restricted positive selection. In this study, we estimated the selection intensity or selection coefficient of rs17822931-A in East Asians by analyzing two microsatellite loci flanking rs17822931 in the African (HapMap-YRI) and East Asian (HapMap-JPT and HapMap-CHB) populations. Assuming a recessive selection model, a coalescent-based simulation approach suggested that the selection coefficient of rs17822931-A had been approximately 0.01 in the East Asian population, and a simulation experiment using a pseudo-sampling variable revealed that the mutation of rs17822931-A occurred 2006 generations (95% credible interval, 1,023-3,901 generations) ago. In addition, we show that absolute latitude is significantly associated with the allele frequency of rs17822931-A in Asian, Native American, and European populations, implying that the selective advantage of rs17822931-A is related to an adaptation to a cold climate. Our results provide a striking example of how local adaptation has played a significant role in the diversification of human traits.

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1 Associate editor: Anne Stone Abstract A nonsynonymous single nucleotide polymorphism (SNP), rs17822931-G/A (538G.A; Gly180Arg), in the ABCC11 gene determines human earwax type (i.e., wet or dry) and is one of most differentiated nonsynonymous SNPs between East Asian and African populations. Login to comment
9 Introduction The type of human earwax is determined by a nonsynonymous single nucleotide polymorphism (SNP), rs17822931-G/A (538G.A; Gly180Arg), in the ABCC11 gene (MIM *607040) (Yoshiura et al. 2006). Login to comment
18 Although it is difficult to statistically examine if natural selection has acted against rs17822931 rather than against rs6500380 owing to the strong LD between them (r2 5 0.91), rs6500380, which is located in intron 12 of LOMP2, seems to have less functional significance compared with rs17822931, which leads to the Gly180Arg amino acid change in ABCC11. Login to comment
185 The functional significance of rs17822931-G/A (G180R) has been recently described (Toyoda et al. 2009). Login to comment

[hide] ABCC11/MRP8 confers pemetrexed resistance in lung ... Cancer Sci. 2010 Nov;101(11):2404-10. doi: 10.1111/j.1349-7006.2010.01690.x. Uemura T, Oguri T, Ozasa H, Takakuwa O, Miyazaki M, Maeno K, Sato S, Ueda R
ABCC11/MRP8 confers pemetrexed resistance in lung cancer.
Cancer Sci. 2010 Nov;101(11):2404-10. doi: 10.1111/j.1349-7006.2010.01690.x., [PMID:20718756]

Abstract [show]
We have previously shown that overexpression of thymidylate synthetase (TS) resulted in pemetrexed (MTA) resistance. To investigate another mechanism of MTA resistance, we investigated the expression of ATP-binding cassette (ABC)-transporters in MTA-resistant lung cancer cell lines and found that the gene and protein expression of ABCC11/MRP8 (ABCC11) was higher in MTA-resistant cells than in the parental cells. The MTA resistant cells showed cross-resistance to methotrexate (MTX), which is a substrate for ABCC11, and intracellular MTX accumulation in MTA-resistant cells was lower than in the parental cells. We then tested the effect of decreasing the expression of ABCC11 by siRNA and found that decreased expression of ABCC11 enhanced MTA cytotoxicity and increased intracellular MTX accumulation in MTA-resistant cells. These findings suggested that ABCC11 directly confers resistance to MTA by enhancing efflux of the intracellular anti-cancer drug. Next, we analyzed the relationship between ABCC11 gene expression and MTA sensitivity of 13 adenocarcinoma cells, but there was no correlation. The ABCC11 gene has been shown to have a functional single-nucleotide polymorphism (SNP), 538G>A. We then classified 13 lung adenocarcinoma cell lines into three groups based on the genotype of this ABCC11 SNP: G/G, G/A and A/A. The A/A group showed a significant reduction in the IC(50) of MTA compared with the combined G/G and G/A groups, indicating that the SNP (538G>A) in the ABCC11 gene is an important determinant of MTA sensitivity. These results showed that ABCC11 may be one of the biomarkers for MTA treatment in adenocarcinomas.

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110 It was recently reported that the ABCC11 gene has a nonsynonymous SNP 538G>A (rs17822931; Gly180Arg), which is important for determination of the type of human earwax that is expressed. Login to comment

[hide] Correlation of axillary osmidrosis to a SNP in the... J Plast Reconstr Aesthet Surg. 2010 Aug;63(8):1369-74. Epub 2009 Jul 21. Inoue Y, Mori T, Toyoda Y, Sakurai A, Ishikawa T, Mitani Y, Hayashizaki Y, Yoshimura Y, Kurahashi H, Sakai Y
Correlation of axillary osmidrosis to a SNP in the ABCC11 gene determined by the Smart Amplification Process (SmartAmp) method.
J Plast Reconstr Aesthet Surg. 2010 Aug;63(8):1369-74. Epub 2009 Jul 21., [PMID:19625231]

Abstract [show]
Axillary osmidrosis (AO) is caused by apocrine glands secretions that are converted to odouriferous compounds by bacteria. A potential link between AO and wet earwax type has been implicated by phenotype-based analysis. Recently, a non-synonymous single nucleotide polymorphism (SNP) 538G> A (Gly180Arg) in the human adenosine triphosphate (ATP)-binding cassette (ABC) transporter ABCC11 gene was found to determine the type of earwax. In this context, we examined a relationship between the degree of AO and the ABCC11 genotype. We have genotyped the SNP 538G> A in a total of 82 Japanese individuals (68 volunteers and 14 AO patients) by both DNA sequencing and the recently developed Smart Amplification Process (SmartAmp). The degree of AO in Japanese subjects was associated with the genotype of the ABCC11 gene as well as wet earwax type. In most AO patients investigated in this study, the G/G and G/A genotypes well correlated with the degree of AO, whereas A/A did not. The specific SmartAmp assays developed for this study provided genotypes within 30 min directly from blood samples. In East Asian countries, AO is rather infrequent. Although the judgement of the degree of AO prevalence is subjective, the SNP 538G> A in ABCC11 is a good genetic biomarker for screening for AO. The SmartAmp method-based genotyping of the ABCC11 gene would provide an accurate and practical tool for guidance of appropriate treatment and psychological management for patients.

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2 Recently, a non-synonymous single nucleotide polymorphism (SNP) 538G> A (Gly180Arg) in the human adenosine triphosphate (ATP)-binding cassette (ABC) transporter ABCC11 gene was found to determine the type of earwax. Login to comment

[hide] A functional ABCC11 allele is essential in the bio... J Invest Dermatol. 2010 Feb;130(2):529-40. Epub 2009 Aug 27. Martin A, Saathoff M, Kuhn F, Max H, Terstegen L, Natsch A
A functional ABCC11 allele is essential in the biochemical formation of human axillary odor.
J Invest Dermatol. 2010 Feb;130(2):529-40. Epub 2009 Aug 27., [PMID:19710689]

Abstract [show]
The characteristic human axillary odor is formed by bacterial action on odor precursors that originate from apocrine sweat glands. Caucasians and Africans possess a strong axillary odor ,whereas many Asians have only a faint acidic odor. In this study, we provide evidence that the gene ABCC11 (MRP8), which encodes an apical efflux pump, is crucial for the formation of the characteristic axillary odor and that a single-nucleotide polymorphism (SNP) 538G --> A, which is prominent among Asian people, leads to a nearly complete loss of the typical odor components in axillary sweat. The secretion of amino-acid conjugates of human-specific odorants is abolished in homozygotic carriers of the SNP, and steroidal odorants and their putative precursors are significantly reduced. Moreover, we show that ABCC11 is expressed and localized in apocrine sweat glands. These data point to a key function of ABCC11 in the secretion of odorants and their precursors from apocrine sweat glands. SNP 538G --> A, which also determines human earwax type, is present on an extended haplotype, which has reached >95% frequency in certain populations in recent human evolution. A strong positive selection in mate choice for low-odorant partners with a dysfunctional ABCC11 gene seems a plausible explanation for this striking frequency of a loss-of-function allele.

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16 The authors reported that a SNP, 538G-A, in ABCC11, leading to a G180R substitution in the corresponding protein, provokes a dry and white earwax phenotype, which is predominant among East Asians (80-95%) and rare among European and African populations (0-3%), which normally have a wet and yellow earwax phenotype. Login to comment

[hide] Earwax, osmidrosis, and breast cancer: why does on... FASEB J. 2009 Jun;23(6):2001-13. Epub 2009 Apr 21. Toyoda Y, Sakurai A, Mitani Y, Nakashima M, Yoshiura K, Nakagawa H, Sakai Y, Ota I, Lezhava A, Hayashizaki Y, Niikawa N, Ishikawa T
Earwax, osmidrosis, and breast cancer: why does one SNP (538G>A) in the human ABC transporter ABCC11 gene determine earwax type?
FASEB J. 2009 Jun;23(6):2001-13. Epub 2009 Apr 21., [PMID:19383836]

Abstract [show]
One single-nucleotide polymorphism (SNP), 538G>A (Gly180Arg), in the ABCC11 gene determines the type of earwax. The G/G and G/A genotypes correspond to the wet type of earwax, whereas A/A corresponds to the dry type. Wide ethnic differences exist in the frequencies of those alleles, reflecting global migratory waves of the ancestors of humankind. We herein provide the evidence that this genetic polymorphism has an effect on the N-linked glycosylation of ABCC11, intracellular sorting, and proteasomal degradation of the variant protein. Immunohistochemical studies with cerumen gland-containing tissue specimens revealed that the ABCC11 WT protein was localized in intracellular granules and large vacuoles, as well as at the luminal membrane of secretory cells in the cerumen gland, whereas granular or vacuolar localization was not detected for the SNP (Arg180) variant. This SNP variant lacking N-linked glycosylation is recognized as a misfolded protein in the endoplasmic reticulum and readily undergoes ubiquitination and proteasomal degradation, which determines the dry type of earwax as a mendelian trait with a recessive phenotype. For rapid genetic diagnosis of axillary osmidrosis and potential risk of breast cancer, we developed specific primers for the SmartAmp method that enabled us to clinically genotype the ABCC11 gene within 30 min.

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1 Yu Toyoda,* Aki Sakurai,*,† Yasumasa Mitani,†,‡ Masahiro Nakashima,§ Koh-ichiro Yoshiura,ʈ Hiroshi Nakagawa,* Yasuo Sakai,¶ Ikuko Ota,†,# Alexander Lezhava,† Yoshihide Hayashizaki,† Norio Niikawa,ʈ, ** and Toshihisa Ishikawa*,†,1 *Department of Biomolecular Engineering, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan; † Omics Science Center (OSC), RIKEN Yokohama Institute, Yokohama, Japan; ‡ K.K. DNAFORM, Yokohama, Japan; § Tissue and Histopathology Section, Atomic Bomb Disease Institute, and ʈ Department of Human Genetics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; ¶ Department of Plastic and Reconstructive Surgery, Fujita Health University, Toyoake, Japan; # Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan; and **Research Institute of Personalized Health Sciences, Health Sciences University of Hokkaido, Hokkaido, Japan ABSTRACT One single-nucleotide polymorphism (SNP), 538G>A (Gly180Arg), in the ABCC11 gene determines the type of earwax. Login to comment
16 Although the biochemical and physiological pathways that regulate the apocrine secretory process are not clearly known, our recent finding that the nonsynonymous SNP 538GϾA (rs17822931; Gly180Arg) in the ABCC11 gene determines the type of earwax has shed light on the novel function of this ABC transporter in apocrine glands (6). Login to comment
23 We have recently reported that one single-nucleotide polymorphism (SNP), 538GϾA (Gly180Arg), in the ABCC11 gene determines the type of earwax (6). Login to comment
31 First, to understand the molecular mechanism determining the earwax type, we investigated the effect of the SNP 538GϾA (Gly180Arg) on the protein expression and intracellular localization of ABCC11. Login to comment
33 In this article, we provide evidence that the SNP 538GϾA (Gly180Arg) variant of human ABCC11 lacking N-linked glycosylation is recognized as a misfolded protein in the endoplasmic reticulum (ER) and readily undergoes proteasomal degradation. Login to comment
72 Generation of ABCC11 variant forms The human ABCC11 WT or G180R cDNA was inserted into the pcDNA3.1/Hygro(-) vector (Invitrogen) between the restriction enzyme sites of XhoI/SalI and HindIII, respectively. Login to comment
73 The resulting expression construct [ABCC11 WT-pcDNA3.1/ Hygro(-)] was used as the template for site-directed mutagenesis to obtain ABCC11 variants, i.e., N838Q, N844Q, and N838Q/N844Q. Login to comment
77 To substitute Gly180 to Arg, Lys, His, Asp, Glu, AL, or Pro in the ABCC11 WT protein, the codon (GGG) encoding the Gly residue in TM1 was changed by site-directed mutagenesis, as described above. Login to comment
116 It is likely that the nonsynonymous SNP 538GϾA (Gly180Arg) greatly affects the cellular localization of the ABCC11 protein in secretory cells. Login to comment
126 B) Human ABCC11 WT or G180R cDNA was inserted into pcDNA3.1/Hygro(-) vector between restriction enzyme sites of XhoI/SalI and HindIII, respectively. Login to comment
161 Since Gly180 or Arg180 residue resides in TM1, this amino acid alteration (Gly180Arg) does not affect immunoreactivity. Login to comment
167 To examine our hypothesis, we substituted Gly180 to Arg, Lys, His, Asp, Glu, AL, and Pro in the ABCC11 WT protein. Login to comment
172 Both the rare mutation and G180R provide the dry type of earwax (6). Login to comment
173 Among the variants tested, only G180R and ⌬27 diminished N-linked glycosylation of ABCC11 (Fig. 6B). Login to comment
176 Clinical genotyping of the SNP 538G>A (Gly180Arg) in the ABCC11 gene by the SmartAmp method We tried to create a clinical method to genotype the SNP 538GϾA in the heman ABCC11 gene. Login to comment
178 Effect of SNP 538GϾA (Gly180Arg) on expression of human ABCC11 protein in Flp-In-293 cells. Login to comment
193 To determine the SNP 538GϾA (Gly180Arg) in the ABCC11 gene, we prepared one set of primers designated TP, FP, BP, OP, and CP (Fig. 7B). Login to comment
78 To substitute Gly180 to Arg, Lys, His, Asp, Glu, AL, or Pro in the ABCC11 WT protein, the codon (GGG) encoding the Gly residue in TM1 was changed by site-directed mutagenesis, as described above. Login to comment
117 It is likely that the nonsynonymous SNP 538Gb0e;A (Gly180Arg) greatly affects the cellular localization of the ABCC11 protein in secretory cells. Login to comment
127 B) Human ABCC11 WT or G180R cDNA was inserted into pcDNA3.1/Hygro(afa;) vector between restriction enzyme sites of XhoI/SalI and HindIII, respectively. Login to comment
162 Since Gly180 or Arg180 residue resides in TM1, this amino acid alteration (Gly180Arg) does not affect immunoreactivity. Login to comment
168 To examine our hypothesis, we substituted Gly180 to Arg, Lys, His, Asp, Glu, AL, and Pro in the ABCC11 WT protein. Login to comment
174 Among the variants tested, only G180R and èc;27 diminished N-linked glycosylation of ABCC11 (Fig. 6B). Login to comment
177 Clinical genotyping of the SNP 538G>A (Gly180Arg) in the ABCC11 gene by the SmartAmp method We tried to create a clinical method to genotype the SNP 538Gb0e;A in the heman ABCC11 gene. Login to comment
179 Effect of SNP 538Gb0e;A (Gly180Arg) on expression of human ABCC11 protein in Flp-In-293 cells. Login to comment
194 To determine the SNP 538Gb0e;A (Gly180Arg) in the ABCC11 gene, we prepared one set of primers designated TP, FP, BP, OP, and CP (Fig. 7B). Login to comment

[hide] MRP class of human ATP binding cassette (ABC) tran... Xenobiotica. 2008 Jul;38(7-8):833-62. Toyoda Y, Hagiya Y, Adachi T, Hoshijima K, Kuo MT, Ishikawa T
MRP class of human ATP binding cassette (ABC) transporters: historical background and new research directions.
Xenobiotica. 2008 Jul;38(7-8):833-62., [PMID:18668432]

Abstract [show]
1. The adenosine triphosphate (ATP) binding cassette (ABC) transporters form one of the largest protein families encoded in the human genome, and more than 48 genes encoding human ABC transporters have been identified and sequenced. It has been reported that mutations of ABC protein genes are causative in several genetic disorders in humans. 2. Many human ABC transporters are involved in membrane transport of drugs, xenobiotics, endogenous substances or ions, thereby exhibiting a wide spectrum of biological functions. According to the new nomenclature of human ABC transporter genes, the 'ABCC' gene sub-family comprises three classes involving multidrug resistance-associated proteins (MRPs), sulfonylurea receptors (SURs), and a cystic fibrosis transmembrane conductance regulator (CFTR). 3. Molecular cloning studies have identified a total of ten members of the human MRP class including ABCC11, ABCC12, and ABCC13 (pseudo-gene) that have recently been characterized. 4. This review addresses the historical background and discovery of the ATP-driven xenobiotic export pumps (GS-X pumps) encoded by MRP genes, biological functions of ABC transporters belonging to the MRP class, and regulation of gene expression of MRPs by oxidative stress.

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223 By using a positional cloning and linkage disequilibrium analysis of genetics of earwax type, Yoshiura et al. (2006) revealed that the non-synonymous SNP (538G>A, Gly180Arg) in the MRP8 gene is the MRP class of human ABC transporters determinant of human earwax type. Login to comment
230 Functional studies with MRP8-expressing LLC-PK1 cells demonstrated that cells expressing MRP8 with allele A (Gly180Arg) show a significantly lower level of cGMP transport, as compared with those expressing MRP8 wild-type with allele G (Yoshiura et al. 2006). Login to comment
233 The non-synonymous SNP of 538 G > A (Gly180Arg) in the MRP8 gene exhibits wide ethnic differences in the allele frequency (Figure 5A). Login to comment

[hide] A SNP in the ABCC11 gene is the determinant of hum... Nat Genet. 2006 Mar;38(3):324-30. Epub 2006 Jan 29. Yoshiura K, Kinoshita A, Ishida T, Ninokata A, Ishikawa T, Kaname T, Bannai M, Tokunaga K, Sonoda S, Komaki R, Ihara M, Saenko VA, Alipov GK, Sekine I, Komatsu K, Takahashi H, Nakashima M, Sosonkina N, Mapendano CK, Ghadami M, Nomura M, Liang DS, Miwa N, Kim DK, Garidkhuu A, Natsume N, Ohta T, Tomita H, Kaneko A, Kikuchi M, Russomando G, Hirayama K, Ishibashi M, Takahashi A, Saitou N, Murray JC, Saito S, Nakamura Y, Niikawa N
A SNP in the ABCC11 gene is the determinant of human earwax type.
Nat Genet. 2006 Mar;38(3):324-30. Epub 2006 Jan 29., [PMID:16444273]

Abstract [show]
Human earwax consists of wet and dry types. Dry earwax is frequent in East Asians, whereas wet earwax is common in other populations. Here we show that a SNP, 538G --> A (rs17822931), in the ABCC11 gene is responsible for determination of earwax type. The AA genotype corresponds to dry earwax, and GA and GG to wet type. A 27-bp deletion in ABCC11 exon 29 was also found in a few individuals of Asian ancestry. A functional assay demonstrated that cells with allele A show a lower excretory activity for cGMP than those with allele G. The allele A frequency shows a north-south and east-west downward geographical gradient; worldwide, it is highest in Chinese and Koreans, and a common dry-type haplotype is retained among various ethnic populations. These suggest that the allele A arose in northeast Asia and thereafter spread through the world. The 538G --> A SNP is the first example of DNA polymorphism determining a visible genetic trait.

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48 We performed an association study of the 118 samples using 37 SNPs within the five-gene interval and found that rs17822931 (538G-A, G180R) in ABCC11 exon 4, rs6500380 (IVS12+7508A-G) in LONPL intron 12 and ss49784070 (IVS14+320A-G) within an Alu-repetitive sequence in LONPL intron 14 showed the lowest P values (o2.0 Â 10-14; Fig. 1). Login to comment
54 Among the SNPs, only rs17822931 is nonsynonymous (G180R); rs6500380 does not create any splicing sites nor affect splicing factor binding motifs or known promoter sequences, and ss49784070 is located within the Alu-repetitive sequence, all supporting rs17822931 as an earwax determinant. Login to comment
88 The G180R substitution in rs17822931 (538G-A) is located at the first transmembrane domain of MRP8. Login to comment

[hide] Association between breast cancer risk and the wil... Anticancer Res. 2010 Dec;30(12):5189-94. Ota I, Sakurai A, Toyoda Y, Morita S, Sasaki T, Chishima T, Yamakado M, Kawai Y, Ishidao T, Lezhava A, Yoshiura K, Togo S, Hayashizaki Y, Ishikawa T, Ishikawa T, Endo I, Shimada H
Association between breast cancer risk and the wild-type allele of human ABC transporter ABCC11.
Anticancer Res. 2010 Dec;30(12):5189-94., [PMID:21187511]

Abstract [show]
BACKGROUND: International mortality and frequency rates for breast cancer have been associated with the wet type of human earwax. It was recently found that earwax type is determined by a single nucleotide polymorphism (SNP), 538G>A (Gly180Arg), in ABCC11. The G allele determines the wet type of earwax as a Mendelian trait with a dominant phenotype. The present study examined the association between the frequency rate of breast cancer and the frequency of the G allele of ABCC11. PATIENTS AND METHODS: Using blood samples from patients with invasive breast cancer (n = 270) and control volunteers (n = 273), the 538G>A SNP in ABCC11 was genotyped using the SmartAmp method. RESULTS: The frequency of the G allele in breast cancer patients was higher than that in healthy controls. The odds ratio for the genotypes (G/G+G/A) to develop breast cancer was estimated to be 1.63 (p-value = 0.026), suggesting that the G allele in ABCC11 is associated with breast cancer risk. CONCLUSION: This study showed that Japanese women with wet earwax have a higher relative risk of developing breast cancer than those with dry earwax. The ABCC11 SNPs that determine these phenotypes should be further investigated in order to obtain insights into the mechanisms by which breast cancer develops and progresses.

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2 It was recently found that earwax type is determined by a single nucleotide polymorphism (SNP), 538G>A (Gly180Arg), in ABCC11. Login to comment
15 Recent studies (4, 5) have provided evidence that the type of earwax is determined by one single nucleotide polymorphism (SNP), 538G>A (Gly180Arg), in the ATP-binding cassette (ABC) transporter ABCC11 located on human chromosome 16q12.1 (6). Login to comment
78 Among those SNPs, one SNP (rs17822931; 538G>A, Gly180Arg) is thought to be a clinically important polymorphism that may related with breast cancer risk. Login to comment

[hide] Mammalian multidrug-resistance proteins (MRPs). Essays Biochem. 2011 Sep 7;50(1):179-207. doi: 10.1042/bse0500179. Slot AJ, Molinski SV, Cole SP
Mammalian multidrug-resistance proteins (MRPs).
Essays Biochem. 2011 Sep 7;50(1):179-207. doi: 10.1042/bse0500179., [PMID:21967058]

Abstract [show]
Subfamily C of the human ABC (ATP-binding cassette) superfamily contains nine proteins that are often referred to as the MRPs (multidrug-resistance proteins). The 'short' MRP/ABCC transporters (MRP4, MRP5, MRP8 and ABCC12) have a typical ABC structure with four domains comprising two membrane-spanning domains (MSD1 and MSD2) each followed by a nucleotide-binding domain (NBD1 and NBD2). The 'long' MRP/ABCCs (MRP1, MRP2, MRP3, ABCC6 and MRP7) have five domains with the extra domain, MSD0, at the N-terminus. The proteins encoded by the ABCC6 and ABCC12 genes are not known to transport drugs and are therefore referred to as ABCC6 and ABCC12 (rather than MRP6 and MRP9) respectively. A large number of molecules are transported across the plasma membrane by the MRPs. Many are organic anions derived from exogenous sources such as conjugated drug metabolites. Others are endogenous metabolites such as the cysteinyl leukotrienes and prostaglandins which have important signalling functions in the cell. Some MRPs share a degree of overlap in substrate specificity (at least in vitro), but differences in transport kinetics are often substantial. In some cases, the in vivo substrates for some MRPs have been discovered aided by studies in gene-knockout mice. However, the molecules that are transported in vivo by others, including MRP5, MRP7, ABCC6 and ABCC12, still remain unknown. Important differences in the tissue distribution of the MRPs and their membrane localization (apical in contrast with basolateral) in polarized cells also exist. Together, these differences are responsible for the unique pharmacological and physiological functions of each of the nine ABCC transporters known as the MRPs.

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276 The 538G>A polymorphism causes a nonߛconservative arginine substitution of Gly180 in the first TMH of MRP8 which appears to disrupt the glycosylation and stability of the protein [70]. Login to comment

[hide] Pharmacogenetics of human ABC transporter ABCC11: ... Front Genet. 2013 Jan 2;3:306. doi: 10.3389/fgene.2012.00306. eCollection 2012. Ishikawa T, Toyoda Y, Yoshiura K, Niikawa N
Pharmacogenetics of human ABC transporter ABCC11: new insights into apocrine gland growth and metabolite secretion.
Front Genet. 2013 Jan 2;3:306. doi: 10.3389/fgene.2012.00306. eCollection 2012., [PMID:23316210]

Abstract [show]
Cell secretion is an important physiological process that ensures smooth metabolic activities and tissue repair as well as growth and immunological functions in the body. Apocrine secretion occurs when the secretory process is accomplished with a partial loss of cell cytoplasm. The secretory materials are contained within secretory vesicles and are released during secretion as cytoplasmic fragments into the glandular lumen or interstitial space. The recent finding that the non-synonymous single nucleotide polymorphisms (SNP) 538G > A (rs17822931; Gly180Arg) in the ABCC11 gene determines the type of earwax in humans has shed light on the novel function of this ABC (ATP-binding cassette) transporter in apocrine glands. The wild-type (Gly180) of ABCC11 is associated with wet-type earwax, axillary osmidrosis, and colostrum secretion from the mammary gland as well as the potential risk of mastopathy. Furthermore, the SNP (538G > A) in the ABCC11 gene is suggested to be a clinical biomarker for the prediction of chemotherapeutic efficacy. The aim of this review article is to provide an overview on the discovery and characterization of genetic polymorphisms in the human ABCC11 gene and to explain the impact of ABCC11 538G > A on the apocrine phenotype as well as the anthropological aspect of this SNP in the ABCC11 gene and patients' response to nucleoside-based chemotherapy.

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3 The secretory materials are contained within secretory vesicles and are released during secretion as cytoplasmic fragments into the glandular lumen or interstitial space.The recent finding that the non-synonymous single nucleotide polymorphisms (SNP) 538G > A (rs17822931; Gly180Arg) in the ABCC11 gene determines the type of earwax in humans has shed light on the novel function of this ABC (ATP-binding cassette) transporter in apocrine glands.The wild-type (Gly180) of ABCC11 is associated with wet-type earwax, axillary osmidrosis, and colostrum secretion from the mammary gland as well as the potential risk of mastopathy. Login to comment
23 A non-synonymous SNP: 538G > A (Gly180Arg), an earwax determinant, is located in exon 4. Login to comment
32 Among those SNPs, one SNP (rs17822931; 538G > A, Gly180Arg) determines the human earwax type (Yoshiura et al., 2006). Login to comment
43 G180R and Ɗ27 are related to the formation of dry-type earwax. Login to comment
141 Therefore, we have most recently carried out a genotyping study of the SNP 538G > A (Gly180Arg) for a total of 543 Japanese women to examine the association between the frequency rate of breast cancer and the allelic frequency of the G allele (WT). Login to comment
204 Although the biochemical and physiological pathways that regulate the apocrine secretory process are not clearly known, our recent findings (Yoshiura et al., 2006; Toyoda et al., 2009; Inoue et al., 2010) that the SNP (538G > A, Gly180Arg) in the ABCC11 gene determines both earwax type and axillary osmidrosis have shed light on the novel function of thisABC transporter in apocrine glands. Login to comment

[hide] Dependence of deodorant usage on ABCC11 genotype: ... J Invest Dermatol. 2013 Jul;133(7):1760-7. doi: 10.1038/jid.2012.480. Epub 2013 Jan 17. Rodriguez S, Steer CD, Farrow A, Golding J, Day IN
Dependence of deodorant usage on ABCC11 genotype: scope for personalized genetics in personal hygiene.
J Invest Dermatol. 2013 Jul;133(7):1760-7. doi: 10.1038/jid.2012.480. Epub 2013 Jan 17., [PMID:23325016]

Abstract [show]
Earwax type and axillary odor are genetically determined by rs17822931, a single-nucleotide polymorphism (SNP) located in the ABCC11 gene. The literature has been concerned with the Mendelian trait of earwax, although axillary odor is also Mendelian. Ethnic diversity in rs17822931 exists, with higher frequency of allele A in east Asians. Influence on deodorant usage has not been investigated. In this work, we present a detailed analysis of the rs17822931 effect on deodorant usage in a large (N approximately 17,000 individuals) population cohort (the Avon Longitudinal Study of Parents and Children (ALSPAC)). We found strong evidence (P=3.7 x 10(-20)) indicating differential deodorant usage according to the rs17822931 genotype. AA homozygotes were almost 5-fold overrepresented in categories of never using deodorant or using it infrequently. However, 77.8% of white European genotypically nonodorous individuals still used deodorant, and 4.7% genotypically odorous individuals did not. We provide evidence of a behavioral effect associated with rs17822931. This effect has a biological basis that can result in a change in the family's environment if an aerosol deodorant is used. It also indicates potential cost saving to the nonodorous and scope for personalized genetics usage in personal hygiene choices, with consequent reduction of inappropriate chemical exposures for some.

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14 In particular, a functional nonsynonymous single-nucleotide polymorphism (SNP; rs17822931), also known as 538 G-A or G180R, determines human earwax type (Yoshiura et al., 2006) and axillary osmidrosis (Nakano et al., 2009; Martin et al., 2010) and is associated with apocrine colostrum secretion from the mammary gland (Miura et al., 2007). Login to comment

[hide] Localization of putative binding sites for cyclic ... BMC Struct Biol. 2013 May 6;13:7. doi: 10.1186/1472-6807-13-7. Honorat M, Terreux R, Falson P, Di Pietro A, Dumontet C, Payen L
Localization of putative binding sites for cyclic guanosine monophosphate and the anti-cancer drug 5-fluoro-2'-deoxyuridine-5'-monophosphate on ABCC11 in silico models.
BMC Struct Biol. 2013 May 6;13:7. doi: 10.1186/1472-6807-13-7., [PMID:23641929]

Abstract [show]
BACKGROUND: The Multidrug Resistance Protein ABCC11/MRP8 is expressed in physiological barriers and tumor breast tissues in which it secretes various substrates including cGMP (cyclic guanosine monophosphate) and 5FdUMP (5-fluoro-2'-deoxyuridine-5'-monophosphate), the active metabolite of the anticancer drug 5-FluoroUracil (frequently included to anticancer therapy).Previously, we described that ABCC11 high levels are associated to the estrogen receptor (ER) expression level in breast tumors and in cell lines resistant to tamoxifen. Consequently, by lowering the intracellular concentration of anticancer drugs, ABCC11 likely promotes a multidrug resistance (MDR) phenotype and decreases efficiency of anticancer therapy of 5FdUMP. Since no experimental data about binding sites of ABCC11 substrate are available, we decided to in silico localize putative substrate interaction sites of the nucleotide derivatives. Taking advantage of molecular dynamics simulation, we also analysed their evolution under computational physiological conditions and during the time. RESULTS: Since ABCC11 crystal structure is not resolved yet, we used the X-ray structures of the mouse mdr3 (homologous to human ABCB1) and of the bacterial homolog Sav1866 to generate two independent ABCC11 homology models in inward- and outward-facing conformations. Based on docking analyses, two putative binding pockets, for cGMP and 5FdUMP, were localized in both inward- and outward-facing conformations. Furthermore, based on our 3D models, and available biochemical data from homologous transporters, we identified several residues, potentially critical in ABCC11 transport function. Additionally, molecular dynamics simulation on our inward-facing model revealed for the first time conformation changes assumed to occur during transport process. CONCLUSIONS: ABCC11 would present two binding sites for cGMP and for 5FdUMP. Substrates likely first bind at the intracellular side of the transmembrane segment while ABCC11 is open forward the cytoplasm (inward-facing conformation). Then, along with conformational changes, it would pass through ABCC11 and fix the second site (close to the extracellular side), until the protein open itself to the extracellular space and allow substrate release.

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100 Insight in the impact of Glycine 180 polymorphism Gly180, found to be inside pocket 2, is prone to G602A SNP (single nucleotide polymorphism) inducing the Gly180Arg mutation which was correlated to earwax type [31], and to colostrum and sweat secretion defaults [32,33]. Login to comment
104 The altered transport of Gly180Arg-mutant ABCC11 can be explained by the additional charge of arginine versus glycine. Login to comment

[hide] Functional characterisation of a SNP in the ABCC11... J Dermatol Sci. 2014 Jan;73(1):23-30. doi: 10.1016/j.jdermsci.2013.08.016. Epub 2013 Sep 10. Harker M, Carvell AM, Marti VP, Riazanskaia S, Kelso H, Taylor D, Grimshaw S, Arnold DS, Zillmer R, Shaw J, Kirk JM, Alcasid ZM, Gonzales-Tanon S, Chan GP, Rosing EA, Smith AM
Functional characterisation of a SNP in the ABCC11 allele - effects on axillary skin metabolism, odour generation and associated behaviours.
J Dermatol Sci. 2014 Jan;73(1):23-30. doi: 10.1016/j.jdermsci.2013.08.016. Epub 2013 Sep 10., [PMID:24076068]

Abstract [show]
BACKGROUND: A single nucleotide polymorphism (SNP), 538G-->A, leading to a G180R substitution in the ABCC11 gene results in reduced concentrations of apocrine derived axillary odour precursors. OBJECTIVE: Determine the axillary odour levels in the SNP ABCC11 genotype variants and to investigate if other parameters associated with odour production are affected. METHODS: Axillary odour was assessed by subjective quantification and gas chromatography headspace analysis. Metabolite profiles, microbiome diversity and personal hygiene habits were also assessed. RESULTS: Axillary odour in the A/A homozygotes was significantly lower compared to the G/A and G/G genotypes. However, the perception-based measures still detected appreciable levels of axillary odour in the A/A subjects. Metabolomic analysis highlighted significant differences in axillary skin metabolites between A/A subjects compared to those carrying the G allele. These differences resulted in A/A subjects lacking specific volatile odourants in the axillary headspace, but all genotypes produced odoriferous short chain fatty acids. Microbiomic analysis revealed differences in the relative abundance of key bacterial genera associated with odour generation between the different genotypes. Deodorant usage indicated a high level of self awareness of axillary odour levels with A/A individuals less likely to adopt personal hygiene habits designed to eradicate/mask its presence. CONCLUSIONS: The SNP in the ABCC11 gene results in lower levels of axillary odour in the A/A homozygotes compared to those carrying the G allele, but A/A subjects still produce noticeable amounts of axillary odour. Differences in axillary skin metabolites, bacterial genera and personal hygiene behaviours also appear to be influenced by this SNP.

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1 Introduction The gene ABCC11, encodes an ATP-driven efflux pump for amphipathic anions [1,2], that displays a single nucleotide polymorphism (SNP), 538G!A, leading to a G180R substitution in the corresponding protein. Login to comment
8 The extent to which the SNP (R180) variant of ABCC11 Journal of Dermatological Science 73 (2014) 23-30 A R T I C L E I N F O Article history: Received 18 March 2013 Received in revised form 1 August 2013 Accepted 30 August 2013 Keywords: Glutamine conjugate Malodour Odoriferous Skin microbiome Skin metabolomics Volatiles A B S T R A C T Background: A single nucleotide polymorphism (SNP), 538G!A, leading to a G180R substitution in the ABCC11 gene results in reduced concentrations of apocrine derived axillary odour precursors. Login to comment

[hide] Identification of volatile organic compounds in hu... J Chromatogr B Analyt Technol Biomed Life Sci. 2014 Mar 15;953-954:48-52. doi: 10.1016/j.jchromb.2014.01.043. Epub 2014 Feb 5. Prokop-Prigge KA, Thaler E, Wysocki CJ, Preti G
Identification of volatile organic compounds in human cerumen.
J Chromatogr B Analyt Technol Biomed Life Sci. 2014 Mar 15;953-954:48-52. doi: 10.1016/j.jchromb.2014.01.043. Epub 2014 Feb 5., [PMID:24572763]

Abstract [show]
We report here the initial examination of volatile organic compounds (VOCs) emanating from human earwax (cerumen). Recent studies link a single nucleotide polymorphism (SNP) in the adenosine triphosphate (ATP) binding cassette, sub-family C, member 11 gene (ABCC11) to the production of different types of axillary odorants and cerumen. ABCC11 encodes an ATP-driven efflux pump protein that plays an important function in ceruminous apocrine glands of the auditory canal and the secretion of axillary odor precursors. The type of cerumen and underarm odor produced by East Asians differ markedly from that produced by non-Asians. In this initial report we find that both groups emit many of the same VOCs but differ significantly in the amounts produced. The principal odorants are volatile organic C2-to-C6 acids. The physical appearance of cerumen from the two groups also matches previously reported ethnic differences, viz., cerumen from East Asians appears dry and white while that from non-Asians is typically wet and yellowish-brown.

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21 changes amino acid 180 in the resultant protein`s polypeptide chain from glycine (G) to arginine (R; G180R), were found to have significantly less of the characteristic axillary odorants than either those who are heterozygous for this change or those who had the wild type gene [10,13]. Login to comment

[hide] Tomatoes cause under-arm odour. Med Hypotheses. 2014 May;82(5):518-21. doi: 10.1016/j.mehy.2014.02.001. Epub 2014 Feb 13. Stewart JC
Tomatoes cause under-arm odour.
Med Hypotheses. 2014 May;82(5):518-21. doi: 10.1016/j.mehy.2014.02.001. Epub 2014 Feb 13., [PMID:24576684]

Abstract [show]
Under arm odour [axillary odour AO, bromidrosis] is a deeply unpleasant problem that can affect a person's self confidence and esteem and reduce social interaction. It is generally managed by good hygiene along with antiperspirants and deodorants, but the axillary apocrine glands may need surgical removal in severe cases of odour. The odour comes from microbial conversion of the apocrine secretions into short chain fatty acids like isovaleric acid and volatile sulphur compounds like 3-sulphanylhexan-1-ol. These can be detected at a few parts per billion to parts per trillion by the human nose so an unhygienic state is soon apparent. Recently genetics have been found to play an important role too as people with the AA variant of the ATP-binding cassette (ABC) transporter gene, ABCC11, do not secrete preodour substrates for bacterial conversion, while those with GA or GG variants do. Hygiene and genetics, are an incomplete explanation though, because the longitudinal ALSPAC study found that there is a mismatch between patients' secretory status, as determined by genetics, and their use of deodorants. This suggests that other metabolic pathways or compounds contribute to the odour. In this paper I propose that under arm odour is commonly caused by terpenes excreted via the axillary apocrine glands. I also show that these come from terpene and carotenoid-rich dietary sources including lycopene, tomatoes, orange peel and the glandular trichomes of tomato plants. These observations suggest that the axillary apocrine glands are a prominent excretory route for terpenes. Considering the quantities eaten, tomatoes are likely to be the main source of dietary terpenes, and under arm odour in turn. This study also shows that lycopene is probably metabolised by beta-carotene 9 10 monooxygenase which cleaves beta-carotene eccentrically at the 9 10 or 9'10' position of the chain. Direct evidence of lycopene metabolism by beta-carotene 9 10 monooxygenase has hitherto been lacking. The study of terpene and carotenoid metabolism can be greatly advanced by analysing the content of axillary gland excretions.

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25 A, which is prominent in Asian populations, changes amino acid 180 from glycine to arginine and creates a misfolded protein that is degraded intracellularly [5,6]. Login to comment

[hide] ABCC11/MRP8 Expression in the Gastrointestinal Tra... Acta Histochem Cytochem. 2014 Jun 28;47(3):85-94. doi: 10.1267/ahc.13040. Epub 2014 Jun 18. Matsumoto H, Tsuchiya T, Yoshiura K, Hayashi T, Hidaka S, Nanashima A, Nagayasu T
ABCC11/MRP8 Expression in the Gastrointestinal Tract and a Novel Role for Pepsinogen Secretion.
Acta Histochem Cytochem. 2014 Jun 28;47(3):85-94. doi: 10.1267/ahc.13040. Epub 2014 Jun 18., [PMID:25320405]

Abstract [show]
ATP-binding cassette (ABC) transporters are involved in chemotherapy resistance. Multidrug-resistance protein 8 (ABCC11/MRP8) is also involved in 5-fluorouracil (5-FU) metabolism. 5-FU and its derivatives are widely used in the treatment of gastrointestinal tract cancers, but little is known about the contribution of ABCC11/MRP8 to gastrointestinal tract and related cancers. Here, we report our investigation of ABCC11/MRP8 expression in normal and cancerous gastrointestinal tract tissues and reveal its novel role in the gastric mucosa. In tissue microarray and surgically resected cancer specimens, immunohistochemical (IHC) staining revealed significantly reduced expression of ABCC11/MRP8 in gastrointestinal tract cancers compared with other cancers. In contrast, strong ABCC11/MRP8 expression was observed in normal gastric mucosa. Additional immuno-fluorescence assays revealed co-localization of ABCC11/MRP8 and pepsinogen I in normal gastric chief cells. Quantitative PCR and Western blot analysis also revealed significant expression of ABCC11/MRP8 in fundic mucosa where the chief cells are mainly located. Furthermore, the ABCC11 mRNA-suppressed NCI-N87 gastric cancer cell line failed to secret pepsinogen I extracellularly. Thus, low expression of ABCC11/MRP8 is consistent with chemotherapeutic regimens using 5-FU and its derivatives in gastrointestinal tract cancers. Our results indicated a novel function of ABCC11/MRP8 in the regulation of pepsinogen I secretion in the normal gastric chief cells.

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25 In summary, a SNP (538G>A, Gly180Arg) in the ABCC11 gene determines the type of earwax, and the GG homozygous and GA heterozygous genotypes correspond to wet earwax [35]. Login to comment

[hide] Ethnic/racial and genetic influences on cerumen od... J Chem Ecol. 2015 Jan;41(1):67-74. doi: 10.1007/s10886-014-0533-y. Epub 2014 Dec 13. Prokop-Prigge KA, Mansfield CJ, Parker MR, Thaler E, Grice EA, Wysocki CJ, Preti G
Ethnic/racial and genetic influences on cerumen odorant profiles.
J Chem Ecol. 2015 Jan;41(1):67-74. doi: 10.1007/s10886-014-0533-y. Epub 2014 Dec 13., [PMID:25501636]

Abstract [show]
This report describes the volatile organic compounds (VOCs) associated with human cerumen (earwax) and the effects of ethnicity/race and variation on the ATP-binding cassette, sub-family C, member 11 gene (ABCC11). A single nucleotide polymorphism (SNP) in ABCC11 affects the cerumen VOC profiles of individuals from African, Caucasian, and Asian descent. Employing gas chromatography/mass spectrometry (GC/MS) we have identified the nature and relative abundance of cerumen VOCs from 32 male donors. Our results show that cerumen contains a complex mixture of VOCs and that the amounts of these compounds vary across individuals as well as across ethnic/racial groups. In six of the seven compounds whose detected concentrations were found to be statistically different across groups, individuals of African descent (AfD) > Caucasian descent (CaD) > Asians descent (AsD). Our findings also reveal that ABCC11 genotype alone does not predict the type and relative levels of volatiles found in human cerumen, and suggest that other biochemical pathways must be involved. Examination of the composition and diversity of external auditory canal microbiota in a small subset of our subject population revealed that the ear microbiota may not be directly correlated with either ethnic group membership or ABCC11 genotype.

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15 It has been reported that a SNP in ABCC11, 538 C࢐T, leads to a G180R substitution in the corresponding K. Login to comment