Phenotype-genotype correlation of in vitro SN-38 (active metabolite of irinotecan) and bilirubin glucuronidation in human liver tissue with UGT1A1 promoter polymorphism

Iyer, Lalitha; Hall, Diana; Das, Soma; Mortell, Melissa A.; Ramı́rez, Jacqueline; Kim, Sarang; Rienzo, Anna Di; Ratain, Mark J.

doi:10.1016/s0009-9236(99)70078-0

Cited by 330 publications

(225 citation statements)

References 37 publications

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“…14,15 A significant correlation between SN-38 and bilirubin glucuronidation has been found, high serum T-Bil concentration seemed to be a reasonably good predictor of lower irinotecan clean rate. [16][17][18] In the present study, the (TA)7 allele was significantly associated with higher T-Bil concentrations, in line with previous reports. 15,19 However, different to Koreans, no association between 211A allele and bilirubin level was found.…”

Section: Intra-ethnic Differences In Genetic Variantssupporting

confidence: 93%

Intra-ethnic differences in genetic variants of the UGT-glucuronosyltransferase 1A1 gene in Chinese populations

et al. 2006

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Variants within the human UGT1A1 gene are associated with irinotecan induced severely adverse reactions and hyperbilirubinemia. Intra-ethnic differences in the genetic variation and haplotypes of UGT1A1 gene have been analyzed in the present study. Relationship between the concentrations of total serum bilirubin (T-bil) and haplotype structure of UGT1A1 in healthy people were also evaluated. We genotyped five functional polymorphisms including À3279T4G and À3156G4A in the enhancer region, (TA)647 in the TATA box, and 211G4A (G71R), 686C4A (P229Q) in the exon1 region of UGT1A1 in three groups of healthy Chinese ethnic populations, consisting of 264 subjects of She origin, 539 of Han origin and 273 of Dong origin. The distribution of À3279T4G, (TA)647, 211G4A of UGT1A1 differed greatly as between the three ethnic groups. All of six haplotypes differed considerably between at least two of the three groups, which highlighted the need to analyze clinically irinotecan toxicity relevant SNPs and haplotypes in a variety of different racial groups within the Chinese population. Total bilirubin concentration in homozygous carriers of the À3279G and (TA)7 allele were significantly higher than those in heterozygous carriers or homozygous carriers of wild-type alleles. Carriers of the variant haplotypes (À3279G; À3156A; (TA)7; 211G; 686C) had higher serum T-Bil concentrations compared with the other groups. Our results indicate that heterogeneity among different ethnic populations is possibly the result of microevolution and is relevant to studies into the effect of tailored drug treatment.

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Section: Intra-ethnic Differences In Genetic Variantssupporting

confidence: 93%

Intra-ethnic differences in genetic variants of the UGT-glucuronosyltransferase 1A1 gene in Chinese populations

et al. 2006

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“…122 Irinotecan {CTP-11 or 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxy camptothecin} is an anticancer drug clinically used in combination with 5-fluorouracil and leucovorin as the first-line treatment of metastatic colorectal cancer. CPT-11 is biotransformed by carboxylesterases into a pharmacologically active metabolite, SN-38 (7-ethyl-10-hydroxycamptothecin), 123 which is responsible for severe toxicity.…”

Section: Ugt1a1mentioning

confidence: 99%

“…This hypothesis is supported by the observation of an inverse relation between SN-38 glucuronidation and the severity of diarrheas occurring in patients treated with irinotecan. 122,124 In a prospective study comprising irinotecan-treated cancer patients, the group of Iyer et al 61 observed that UGT1A1 promoter activity influences the extent of SN-38-G formation and is associated with the incidence of adverse reactions, mostly neutropenia and diarrhea. A retrospective clinical study of Japanese cancer patients revealed an association between genetic Pharmacogenomics of human UGT enzymes C Guillemette In the case of rare hyperbilirubinemia, as in CN type I, the UGT1A1*28 variant promoter does not seem to play a significant role, while in the case of CN type II, the presence of the *28 allele was shown to affect the clinical characteristics of the disease.…”

Section: Ugt1a1mentioning

confidence: 99%

Pharmacogenomics of human UDP-glucuronosyltransferase enzymes

2003

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UDP-glucuronosyltransferase (UGT) enzymes comprise a superfamily of key proteins that catalyze the glucuronidation reaction on a wide range of structurally diverse endogenous and exogenous chemicals. Glucuronidation is one of the major phase II drug-metabolizing reactions that contributes to drug biotransformation. This biochemical process is also involved in the protection against environmental toxicants, carcinogens, dietary toxins and participates in the homeostasis of numerous endogenous molecules, including bilirubin, steroid hormones and biliary acids. Over the years, significant progress was made in the field of glucuronidation, especially with regard to the identification of human UGTs, study of their tissue distribution and substrate specificities. More recently, the degree of allelic diversity has also been revealed for several human UGT genes. Some polymorphic UGTs have demonstrated a significant pharmacological impact in addition to being relevant to drug-induced adverse reactions and cancer susceptibility. This review focuses on human UGTs, the description of the nature of polymorphic variations and their functional impact. The pharmacogenomic implication of polymorphic UGTs is presented, more specifically the role of UGT polymorphisms in modifying cancer risk and their impact on individual risk to drug-induced toxicities.

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“…[13][14][15] While the primary selective pressure for UGT1A enzyme function may have been metabolism of endogenous molecules, UGT1A function is necessary for elimination of exogenous compounds such as the anti-cancer drug irinotecan. [16][17][18] The same common UGT1A1 variants associated with mild elevations of serum bilirubin are associated with diminished in vitro glucuronidation of the active irinotecan metabolite, SN-38, [19][20][21][22] and prolonged exposure and increased toxicity in patients receiving this agent. [23][24][25] As shown by Sai et al, 25 re-sequencing of the UGT1A1 gene in 85 Japanese patients treated with irinotecan confirmed that the haplotypes containing lower expression variants were associated with both a low SN-38G/SN-38 AUC ratio and elevated pretreatment bilirubin concentration.…”

Section: Introductionmentioning

confidence: 99%

Comparative genomics analysis of human sequence variation in the UGT1A gene cluster

et al. 2005

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Common polymorphisms within the human UGT1A gene locus are associated with irinotecan and tranilast toxicity. To uncover additional functional variation across this gene cluster, cross-species sequence comparisons were performed. Evolutionarily conserved segments (a total of 47.1 kb) were re-sequenced in 24 African-American, 24 European-American, and 24 Asian individuals, and 381 segregating sites (including 123 singletons) were identified. Highly conserved coding sites were less likely to be polymorphic than diverged sites (Po0.0001) but this pattern was not observed at noncoding sites (P ¼ 0.1025). Among coding variants, the distribution of those computationally predicted to affect function was skewed toward low frequencies. Some alleles occurred at similar frequencies in each population; others had wide disparities. Although strong linkage disequilibrium was detected among the hepatically expressed genes, the degree of linkage disequilibrium varied among populations. These results suggest that rare functional gene variants and inter-population variability must be considered in the interpretation of association studies between UGT1A and drug metabolism/toxicity phenotypes.

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Phenotype-genotype correlation of in vitro SN-38 (active metabolite of irinotecan) and bilirubin glucuronidation in human liver tissue with UGT1A1 promoter polymorphism

Abstract: The results indicate a significant association of UGT1A1 phenotype and genotype based on in vitro phenotypic measurements. The clinical significance of our finding remains to be established.

Cited by 330 publications

References 37 publications

Intra-ethnic differences in genetic variants of the UGT-glucuronosyltransferase 1A1 gene in Chinese populations

Intra-ethnic differences in genetic variants of the UGT-glucuronosyltransferase 1A1 gene in Chinese populations

Pharmacogenomics of human UDP-glucuronosyltransferase enzymes

Comparative genomics analysis of human sequence variation in the UGT1A gene cluster

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