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

Background: Hepatic uridine diphosphate glucuronosyltransferase (UGT) isofo rm 1A1 (UGT1A1) is primarily responsible for the glucuronidation of SN-38 ( 7-ethyl-10-hydroxycamptothecin), the active metabolite of the anticancer ag ent irinotecan, UGT1A1, also catalyzing the glucuronidation of bilirubin, h as been shown to have reduced activity in Gilbert's syndrome, The presence of an additional TA repeat [(TA)(7)TAA] in the TATA sequence of UGT1A1 has been associated with Gilbert's syndrome, Objective: To evaluate the relationship between UGT1A1 phenotypic activity and UGT1A1 promoter polymorphism, Methods: Phenotypic measurements included in vitro SN-38 and bilirubin gluc uronidation in human liver microsomes (n = 44), A recently developed genoty ping test was used to determine TATA sequence polymorphisms in UGT1A1, Geno types were assigned as follows: 7/7, homozygous for the (TA)(7)TAA allele; 6/6, homozygous for the (TA)(6)TAA allele; and 6/7, heterozygous with 1 of each allele, Results: Nine percent of screened liver samples were found to be homozygous for allele 7 (7/7), 43% were homozygous for allele 6 (6/6), and 48% were h eterozygous (6/7), Frequencies of (TA)(7)TAA and (TA)(6)TAA alleles were 0. 33 and 0.67, respectively, A significant trend toward a decrease in SN-38 a nd bilirubin glucuronidation rates was found as the number of TA repeats in creased (6/6 > 6/7 > 7/7), Glucuronidation rates of both substrates were si gnificantly lower in the 7/7 and 6/7 groups compared with the 6/6 group, Conclusions The results indicate a significant association of UGT1A1 phenot ype and genotype based on in vitro phenotypic measurements, The clinical si gnificance of our finding remains to be established.