ABCB1 p.Gly211Ala
| Predicted by SNAP2: | A: N (57%), C: N (53%), D: D (71%), E: D (80%), F: D (71%), H: D (71%), I: D (71%), K: D (85%), L: D (71%), M: D (75%), N: D (59%), P: D (85%), Q: D (71%), R: D (85%), S: N (78%), T: D (66%), V: D (66%), W: D (85%), Y: D (71%), |
| 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] 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.
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No. Sentence Comment
189 The mutation G211A (UGT1A1*6) has a meaningful role in the Asian population where is more widespread than in Caucasians [86].
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ABCB1 p.Gly211Ala 12769780:189:13
status: NEW190 UGT1A1*6 allele is characterised by a mutation on exon 1 (G211A) so it has an effect on the protein sequence leading to the aminoacid substitution Gly71Arg.
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ABCB1 p.Gly211Ala 12769780:190:58
status: NEW217 UGT1A1 Polymorphisms Involved in Gilbert Syndrome Polymorphism Mutation Effect Location UGT1A1*28 (TA)6→(TA)7 lower expression Promoter UGT1A1*6 G211A Gly71Arg Exon 1 UGT1A1*27 C686A Pro229Gln Exon1 UGT1A1*29 C1099G Arg367Gly Exon 4 UGT1A1*7 T1456G Tyr486Asp Exon 5 tissues and a sequence homology of 49% only [91].
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ABCB1 p.Gly211Ala 12769780:217:152
status: NEW[hide] Genetic factors influencing severe atazanavir-asso... Clin Infect Dis. 2010 Jul 1;51(1):101-6. Park WB, Choe PG, Song KH, Jeon JH, Park SW, Kim HB, Kim NJ, Oh MD, Choe KW
Genetic factors influencing severe atazanavir-associated hyperbilirubinemia in a population with low UDP-glucuronosyltransferase 1A1*28 allele frequency.
Clin Infect Dis. 2010 Jul 1;51(1):101-6., 2010-07-01 [PMID:20504240]
Abstract [show]
BACKGROUND: High prevalence of severe atazanavir-associated hyperbilirubinemia in Asians with low prevalence of the UDP-glucuronosyltransferase (UGT)1A1*28 polymorphism suggests the importance of genetic factors other than UGT1A1*28 for atazanavir-associated hyperbilirubinemia in these populations. METHODS: Serum bilirubin levels were measured in 129 Korean human immunodeficiency virus-infected patients 3 months after initiation of atazanavir (400 mg per day) with good adherence to medication. The multidrug resistance gene 1 (MDR1) C3435T and G2677T/A variations and UGT1A1*6 and *28 were examined by direct sequencing of DNA from peripheral whole blood samples. The associations between genetic polymorphisms and severe (grade 3-4) hyperbilirubinemia were evaluated using multivariate logistic regression analysis including demographic and clinical variables. RESULTS: The median patient age was 39 years (interquartile range, 34-51 years), and 91% were men. At baseline, the median CD4 cell count was 261 cells/microL (interquartile range, 181-405 cells/microL). Severe hyperbilirubinemia was detected in 27 patients (21%). The independent risk factors for severe hyperbilirubinemia were low baseline CD4 cell count (adjusted odds ratio per 10 cells/microL increase, 0.97; 95% confidence interval, 0.94-0.99), UGT1A1*28 (adjusted odds ratio, 4.15; 95% confidence interval, 1.46-11.84), and MDR1 G2677T/A (adjusted odds ratio, 9.65; 95% confidence interval, 1.09-85.61). Of 19 patients with wild-type alleles for both MDR1 2677 and UGT1A1*28, none developed severe hyperbilirubinemia. CONCLUSION: The MDR1 G2677T/A variation and UGT1A1*28 are independent risk factors for severe atazanavir-associated hyperbilirubinemia in Korean human immunodeficiency virus-infected patients.
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31 The UGT1A1*6 polymorphism (G211A, G71R), which is common in some Asians (13%-23%) and rare in Caucasians (0.1%) [3], results in an ~70% reduction in the rate of bilirubin glucuronidation in vitro [11] and is associated with Gilbert syndrome in Asians, irrespective of the UGT1A1*28 allele [6, 12].
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ABCB1 p.Gly211Ala 20504240:31:27
status: NEW[hide] Genetic profile of patients with epilepsy on first... Pharmacogenomics. 2010 Jul;11(7):927-41. Grover S, Gourie-Devi M, Baghel R, Sharma S, Bala K, Gupta M, Narayanasamy K, Varma B, Gupta M, Kaur K, Talwar P, Kaur H, Giddaluru S, Sharma A, Brahmachari SK, Indian Genome Variation Consortium, Kukreti R
Genetic profile of patients with epilepsy on first-line antiepileptic drugs and potential directions for personalized treatment.
Pharmacogenomics. 2010 Jul;11(7):927-41., [PMID:20602612]
Abstract [show]
BACKGROUND: The first-line antiepileptic drugs, although affordable and effective in the control of seizures, are associated with adverse drug effects, and there is large interindividual variability in the appropriate dose at which patients respond favorably. This variability may partly be explained by functional consequences of genetic polymorphisms in the drug-metabolizing enzymes, such as the CYP450 family, microsomal epoxide hydrolase and UDP-glucuronosyltransferases, drug transporters, mainly ATP-binding cassette transporters, and drug targets, including sodium channels. The purpose of this study was to determine the allele and genotype frequencies of such genetic variants in patients with epilepsy from North India administered first-line antiepileptic drugs, such as phenobarbitone, phenytoin, carbamazepine and valproic acid, and compare them with worldwide epilepsy populations. MATERIALS & METHODS: SNP screening of 19 functional variants from 12 genes in 392 patients with epilepsy was carried out, and the patients were classified with respect to the metabolizing rate of their drug-metabolizing enzymes, efflux rate of drug transporters and sensitivity of drug targets. RESULTS: A total of 16 SNPs were found to be polymorphic, and the allelic frequencies for these SNPs were in conformance with Hardy-Weinberg equilibrium. Among all the polymorphisms studied, functional variants from genes encoding CYP2C19, EPHX1, ABCB1 and SCN1A were highly polymorphic in North Indian epilepsy patients, and might account for differential drug response to first-line antiepileptic drugs. CONCLUSION: Interethnic differences were elucidated for several polymorphisms that might be responsible for differential serum drug levels and optimal dose requirement for efficacious treatment.
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No. Sentence Comment
140 UGT1A1*6 is one of the most common UGT1A1 coding variants, characterized by a G211A transition corresponding to codon 71 in exon 1, which changes glycine to arginine.
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ABCB1 p.Gly211Ala 20602612:140:78
status: NEW[hide] Validation of in vitro cell models used in drug me... Toxicol Appl Pharmacol. 2006 Feb 15;211(1):1-10. Epub 2005 Jun 21. Brandon EF, Bosch TM, Deenen MJ, Levink R, van der Wal E, van Meerveld JB, Bijl M, Beijnen JH, Schellens JH, Meijerman I
Validation of in vitro cell models used in drug metabolism and transport studies; genotyping of cytochrome P450, phase II enzymes and drug transporter polymorphisms in the human hepatoma (HepG2), ovarian carcinoma (IGROV-1) and colon carcinoma (CaCo-2, LS180) cell lines.
Toxicol Appl Pharmacol. 2006 Feb 15;211(1):1-10. Epub 2005 Jun 21., [PMID:15975613]
Abstract [show]
Human cell lines are often used for in vitro biotransformation and transport studies of drugs. In vivo, genetic polymorphisms have been identified in drug-metabolizing enzymes and ABC-drug transporters leading to altered enzyme activity, or a change in the inducibility of these enzymes. These genetic polymorphisms could also influence the outcome of studies using human cell lines. Therefore, the aim of our study was to pharmacogenotype four cell lines frequently used in drug metabolism and transport studies, HepG2, IGROV-1, CaCo-2 and LS180, for genetic polymorphisms in biotransformation enzymes and drug transporters. The results indicate that, despite the presence of some genetic polymorphisms, no real effects influencing the activity of metabolizing enzymes or drug transporters in the investigated cell lines are expected. However, this characterization will be an aid in the interpretation of the results of biotransformation and transport studies using these in vitro cell models.
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No. Sentence Comment
56 (2000), was used to determine the *6 (G211A), *7 (T1456G), *27 (C686A), *28 (A(TA)6TAA to A(TA)7TAA), *33 (A(TA)6TAA to A(TA)5TAA), *34 (A(TA)6TAA to A(TA)8TAA) and *29 (C1099G) polymorphisms in the UGT1A1 gene.
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ABCB1 p.Gly211Ala 15975613:56:38
status: NEW55 (2000), was used to determine the *6 (G211A), *7 (T1456G), *27 (C686A), *28 (A(TA)6TAA to A(TA)7TAA), *33 (A(TA)6TAA to A(TA)5TAA), *34 (A(TA)6TAA to A(TA)8TAA) and *29 (C1099G) polymorphisms in the UGT1A1 gene.
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ABCB1 p.Gly211Ala 15975613:55:38
status: NEW