ABCC12 p.Thr307Cys
| Predicted by SNAP2: | A: N (61%), C: N (53%), D: D (63%), E: D (53%), F: D (71%), G: N (72%), H: D (53%), I: D (66%), K: D (59%), L: D (66%), M: D (63%), N: N (82%), P: D (63%), Q: N (78%), R: N (53%), S: N (87%), V: D (66%), W: D (71%), Y: D (66%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, V: D, W: D, Y: D, |
[switch to compact view]
Comments [show]
None has been submitted yet.
[hide] Pharmacogenetics of irinotecan. Curr Med Chem Anticancer Agents. 2003 May;3(3):225-37. Toffoli G, Cecchin E, Corona G, Boiocchi M
Pharmacogenetics of irinotecan.
Curr Med Chem Anticancer Agents. 2003 May;3(3):225-37., [PMID:12769780]
Abstract [show]
Pharmacogenetics focuses on intersubjects variation in therapeutic drug effects and toxicity depending on genetic polymorphisms. This is particularly interesting in oncology since anticancer drugs usually have a narrow margin of safety. Irinotecan [7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin] is used in cancer chemotherapy as a topoisomerase I inhibitor and it is characterised by a sometimes unpredictable severe toxicity. It is mostly intestinal with nausea, vomit and diarrhoea or haematologic with leuko-thrombocytopenia. Its complex metabolism involves many proteins. Human carboxylesterase isoforms 1 and 2 (hCE1, hCE2) activate irinotecan to its metabolite SN-38 (7-ethyl-10-hydroxycamptothecin); cytochrome P450 isoforms 3A4 and 3A5 (CYP3A4, CYP3A5) mediate the oxidation of the parental compound to irinotecan; uridino-glucuronosil transferase isoform 1A1 (UGT1A1) catalyses glucuronidation of SN-38; the multi-resistance protein isoform 2 (MRP2) allows the cellular excretion of the SN-38 glucuronide (SN-38G) and the multi-drug resistance gene (MDR1), encoding for P-glycoprotein, is responsible for the excretion of irinotecan from the cell. Polymorphic structures in the genes encoding for all these proteins have been described. In particular, the UGT1A1*28 allele has been associated with an increased toxicity after irinotecan chemotherapy. Classical parameters used in the clinic, such as body-surface area, have no longer a meaningful correlation with clinical outcome. Hence it emerges the importance of studying the individual genotype to predict the toxicity and efficacy of irinotecan and to individualise therapy. In this review, we summarise the new developments on the study of the pharmacogenetics of irinotecan, stressing its importance in drug cytotoxic effect.
Comments [show]
None has been submitted yet.
No. Sentence Comment
261 Also T307C and G1199A are mutations causing a significant aminoacid change (Phe103Leu and Ser400Asn respectively) in important zones of the protein and possibly affecting the P-gp efficacy.
X
ABCC12 p.Thr307Cys 12769780:261:5
status: NEW[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.
Comments [show]
None has been submitted yet.
No. Sentence Comment
6832 Nucleotide Change Amino Acid Change In Vitro Function Protein Expression/ Localization ABCB1 MDR1 A61G N21D ↔ N.D. T307C F103L N.D. N.D. G1199A S400N 1↔ Normal C2005T R669C ↔ N.D. G2677T A893S 21↔ Normal G2677A A893T 1↔ Notmal T3421A S1141T 2↔ N.D. C3435T I1145I 2↔ N.D. G3751A V1251I 2 N.D. 2, reduced function; 1, increased function; ↔, no change in function; N.D. not determined.
X
ABCC12 p.Thr307Cys 20103563:6832:122
status: NEW6829 Nucleotide Change Amino Acid Change In Vitro Function Protein Expression/ Localization ABCB1 MDR1 A61G N21D N.D. T307C F103L N.D. N.D. G1199A S400N 1 Normal C2005T R669C N.D. G2677T A893S 21 Normal G2677A A893T 1 Notmal T3421A S1141T 2 N.D. C3435T I1145I 2 N.D. G3751A V1251I 2 N.D. 2, reduced function; 1, increased function; , no change in function; N.D. not determined.
X
ABCC12 p.Thr307Cys 20103563:6829:121
status: NEW