ABCMdb

ABCB4 p.Ile764Leu

Predicted by SNAP2:	A: N (87%), C: N (87%), D: D (71%), E: D (66%), F: N (87%), G: N (61%), H: D (63%), K: D (66%), L: N (93%), M: N (66%), N: D (63%), P: D (71%), Q: D (59%), R: D (66%), S: N (57%), T: N (87%), V: N (97%), W: D (66%), Y: N (53%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, K: D, L: N, M: N, N: D, P: D, Q: D, R: D, S: D, T: D, V: N, W: D, Y: D,

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[hide] Mutations and polymorphisms in the bile salt expor... Pharmacogenet Genomics. 2007 Jan;17(1):47-60. Lang C, Meier Y, Stieger B, Beuers U, Lang T, Kerb R, Kullak-Ublick GA, Meier PJ, Pauli-Magnus C
Mutations and polymorphisms in the bile salt export pump and the multidrug resistance protein 3 associated with drug-induced liver injury.
Pharmacogenet Genomics. 2007 Jan;17(1):47-60., [PMID:17264802]

Abstract [show]
OBJECTIVES: Increasing evidence suggests that a genetically determined functional impairment of the hepatocellular efflux transporters bile salt export pump (BSEP, ABCB11) and multidrug resistance protein 3 (MDR3, ABCB4) play a pathophysiological role in the development of drug-induced liver injury. The aim of this study was therefore to describe the extent of genetic variability in ABCB11 and ABCB4 in patients with drug-induced liver injury and to in vitro functionally characterize newly detected ABCB11 mutations and polymorphisms. METHODS: ABCB11 and ABCB4 were sequenced in 23 patients with drug-induced cholestasis and 13 patients with drug-induced hepatocellular injury. Ninety-five healthy Caucasians served as the control group. Reference and mutant BSEP were expressed in Sf9 cells and ATP-dependent transport of [H]-taurocholate was measured in a rapid filtration assay. RESULTS: Four highly conserved nonsynonymous mutations were specific for drug-induced liver injury [ABCB11: D676Y (drug-induced cholestasis) and G855R (drug-induced cholestasis); ABCB4: I764L (drug-induced cholestasis) and L1082Q (drug-induced hepatocellular injury)]. Furthermore, a polymorphism in exon 13 of ABCB11 (V444A), which is associated with decreased hepatic BSEP expression was significantly more frequent in drug-induced cholestasis patients than in drug-induced hepatocellular injury patients and healthy controls (76 versus 50 and 59% in drug-induced cholestasis patients, drug-induced hepatocellular injury patients and healthy controls, respectively; P<0.05). The in-vitro transport activity of the V444A and the D676Y BSEP constructs was similar, whereas the G855R mutation was nonfunctional. CONCLUSION: In summary, our data support a role of ABCB11 and ABCB4 mutations and polymorphisms in drug-induced cholestasis. Genotyping of selected patients with acquired cholestasis might help to identify individuals with a genetic predisposition.

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5 Results Four highly conserved nonsynonymous mutations were specific for drug-induced liver injury [ABCB11: D676Y (drug-induced cholestasis) and G855R (drug-induced cholestasis); ABCB4: I764L (drug-induced cholestasis) and L1082Q (drug-induced hepatocellular injury)]. Login to comment
142 With the exception of the I764L, which was located in the eighth transmembrane domain of MDR3, all other nonsynonymous variants were Table 6 ABCB4 (MDR3)1 variant sites in drug-induced liver injury Amplicon DNA position cDNA position Nucleotide reference Nucleotide variant AA change AF DC (n = 46) AF DH (n = 26) AF controls (n = 112) Amplicon - 3 Intron - 4 - 394 T G 0.02 0.00 0.05 Amplicon - 3 Intron - 4 - 197 G T 0.00 0.04 0.00 Amplicon - 3 Exon - 3 - 410 T C Noncoding 0.02 0.00 0.05 Amplicon - 2 Exon - 2 - 228 C T Noncoding 0.04 0.08 0.11 Amplicon - 1 Intron - 2 - 221 C T 0.04 0.08 0.11 Amplicon - 1 Intron - 2 - 204 A G 0.04 0.08 0.13 Amplicon 1 Intron - 1 - 301 C G 0.07 0.08 0.17 Amplicon 1 Intron - 1 - 220 C T 0.02 0.00 0.05 Amplicon 1 Intron - 1 - 201 C G 0.04 0.08 0.13 Amplicon 1 Intron - 1 - 184 T C 0.33 0.46 0.26 Amplicon 4 Exon 4 175 C T syn 0.05 0.08 0.13 Amplicon 5 Intron 4 - 61 C T 0.11 0.08 0.03 Amplicon 5 Intron 5 113 A G 0.07 0.08 0.16 Amplicon 6 Intron 5 - 62 AGAAA delAGAAA 0.05 0.04 0.08 Amplicon 6 Intron 5 - 50 GAAA delGAAA 0.02 0.00 0.00 Amplicon 6 Exon 6 504 C T syn 0.62 0.46 0.57 Amplicon 6 Exon 6 523 A G T175A_c 0.02 0.00 0.03 Amplicon 8 Exon 8 711 A T syn 0.07 0.08 0.15 Amplicon 11 Intron10 - 43 T C 0.02 0.00 0.00 Amplicon 12 Intron 11 - 88 T delT 0.05 0.00 0.07 Amplicon 12 Intron 11 - 81 T delT 0.04 0.04 0.00 Amplicon 12 Exon 12 1314 G A syn 0.00 0.04 0.00 Amplicon 12 Intron 12 130 G T 0.08 0.04 0.06 Amplicon 13 Intron 12 - 40 G A 0.02 0.00 0.05 Amplicon 15 Intron 14 - 39 A G 0.02 0.08 0.01 Amplicon 15 Exon 15 1769 G A R590Q_c 0.02 0.00 0.01 Amplicon 16 Exon 16 1954 A G R652G 0.09 0.04 0.07 Amplicon 16 Intron 16 55 A G 0.09 0.04 0.05 Amplicon 17 Intron 17 16 T C 0.03 0.00 0.05 Amplicon 18 Exon 18 2290 A C I764L_c 0.02 0.00 0.00 Amplicon 20 Intron 20 40 A G 0.11 0.00 0.06 Amplicon 23 Intron 23 70 G T 0.00 0.04 0.00 Amplicon 25 Exon 25 3245 T A L1082Q_c 0.00 0.04 0.00 Amplicon 27 Intron 26 - 16 T C 0.35 0.58 0.92 Amplicon 28 Intron 27 - 72 T C 0.11 0.00 0.07 cDNA numbers are relative to the ATG site and based on the cDNA sequence from GenBank accession number NM_000443.2. Login to comment
150 Six variant sites were specific for patients with drug-induced liver injury, including three intronic and three coding region changes (synonymous: exon 12: 1314G > A; nonsynonymous: exon 18: 2290A > C-I764L and exon 25: 3245T > A-L1082Q). Login to comment
151 The heterozygous I764L mutation was observed in a patient with DC taking risperidone (no. Login to comment
163 The estimated IC50 was 50 and 60 mmol/l for reference BSEP Fig. 4 Extracellular I764L T175A R652G R590Q Cytoplasm L1082Q Secondary structure of multidrug resistance protein 3 (MDR3) with nonsynonymous coding region variants. Login to comment
200 The conserved I764L site encountered in a heterozygous patient with risperidone-induced cholestasis was located in the transmembrane domain of MDR3, a region that exhibits only very little variation in members of the ABC superfamily of transporters [29]. Login to comment

[hide] Genetic determinants of drug-induced cholestasis a... Semin Liver Dis. 2010 May;30(2):147-59. Epub 2010 Apr 26. Pauli-Magnus C, Meier PJ, Stieger B
Genetic determinants of drug-induced cholestasis and intrahepatic cholestasis of pregnancy.
Semin Liver Dis. 2010 May;30(2):147-59. Epub 2010 Apr 26., [PMID:20422497]

Abstract [show]
Intrahepatic cholestasis of pregnancy and drug-induced cholestasis are two clinically important forms of acquired cholestatic liver disease. The understanding of the underlying mechanisms of acquired cholestasis has recently made considerable progress by the identification of canalicular ATP-binding cassette (ABC) transporters as likely targets for these forms of cholestasis. Cholestasis of pregnancy is linked to estrogen and progesterone metabolites. These metabolites have been shown to impair the bile salt export pump (BSEP) function by an indirect mechanism. In addition, genetic variants (as well as mutants) of the genes coding for the phosphatidylcholine translocator MDR3 and BSEP and for the farnesoid X receptor, which is critical in the transcriptional activation of MDR3 ( ABCB4) and BSEP ( ABCB11) have been associated with intrahepatic cholestasis of pregnancy. The pathogenesis of drug-induced liver injury encompasses a wide spectrum of mechanisms, some of which are still poorly understood. BSEP is now known to be subject to drug inhibition in susceptible patients. Information on genetic factors rendering individuals susceptible to inhibition of BSEP by drugs or their metabolites is still scarce. Besides rare mutations that have been linked to drug-induced cholestasis, the common p.V444A polymorphism of BSEP has been identified as a potential risk factor. In this review, the authors summarize key concepts of physiology of bile formation, diagnostic principles to indentify these forms of acquired cholestasis, as well as pathogenetic mechanisms leading to intrahepatic cholestasis of pregnancy or drug-induced cholestasis. In addition, they review the current knowledge on genetic susceptibility factors for these two forms of cholestasis.

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125 Specifically, full-length sequencing of ABCB11 and ABCB4 revealed a heterozygous p.D676Y mutation in BSEP observed in a patient taking fluvas- tatin and a heterozygous p.I764L mutation in MDR3 observed in a patient taking risperidone:115 both suffered from hepatocellular cholestasis. Login to comment
127 In the case of BSEP, in vitro taurocholate transport was unchanged for the mutated protein whereas the impact of the p.I764L mutation on MDR3 expression and function was not investigated. Login to comment

[hide] Tacrine-induced liver damage: an analysis of 19 ca... Pharmacogenet Genomics. 2007 Dec;17(12):1091-100. Alfirevic A, Mills T, Carr D, Barratt BJ, Jawaid A, Sherwood J, Smith JC, Tugwood J, Hartkoorn R, Owen A, Park KB, Pirmohamed M
Tacrine-induced liver damage: an analysis of 19 candidate genes.
Pharmacogenet Genomics. 2007 Dec;17(12):1091-100., [PMID:18004213]

Abstract [show]
OBJECTIVES: Tacrine, the first acetylcholinesterase inhibitor used in the treatment of Alzheimer's disease, is associated with transaminase elevation in up to 50% of patients. The mechanism of tacrine-induced liver damage is not fully understood, but earlier studies have suggested that genetic factors may play a role. Our aim was to investigate whether single-nucleotide polymorphisms (SNPs) in 19 candidate genes were associated with tacrine-induced liver damage. METHODS: Sixty-nine patients of Caucasian origin treated with tacrine for Alzheimer's disease were investigated by genotyping 241 SNPs in 19 candidate genes potentially related to hepatotoxicity. The association with ABCB4 [which encodes MultiDrug Resistance Protein 3 (MDR3)] was explored in transepithelial transport studies using the ABCB4-transfected pig kidney epithelial cell line (LLC-PK1). RESULTS: The strongest association between alanine aminotransferase levels and three SNPs within ATP-binding cassette, subfamily B (MDR/TAP), member 4 (ABCB4) (uncorrected P=0.0005) was not significant after adjusting for multiple testing. No association was demonstrated with ATP-binding cassette, subfamily B (MDR/TAP), member 1 (ABCB1) or carnitine O-octanoyltransferase (CROT) which are located adjacent to ABCB4. Using the transepithelial transport system we failed to show a difference in tacrine accumulation between ABCB4-transfected and parental cell lines. The association with ABCB4 warrants further testing using either another population and/or functional studies.

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196 Two ABCB4 nonsynonymous SNPs (I764L and L1082Q) were specific for drug-induced cholestasis and hepatocellular injury, respectively. Login to comment