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

Abstract

Background Hepatic uridine diphosphate glucuronosyltransferase (UGT) isoform 1A1 (UGT1A1) is primarily responsible for the glucuronidation of SN‐38 (7‐ethyl‐10‐hydroxycamptothecin), the active metabolite of the anticancer agent irinotecan. UGT1A1, also catalyzing the glucuronidation of bilirubin, has 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 glucuronidation in human liver microsomes (n = 44). A recently developed genotyping test was used to determine TATA sequence polymorphisms in UGT1A1. Genotypes 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 heterozygous (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 and bilirubin glucuronidation rates was found as the number of TA repeats increased (6/6 > 6/7 > 7/7). Glucuronidation rates of both substrates were significantly lower in the 7/7 and 6/7 groups compared with the 6/6 group. Conclusions 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. Clinical Pharmacology & Therapeutics (1999) 65, 576–582; doi: