Novel functional polymorphisms in the UGT1A7 and UGT1A9 glucuronidating enzymes in Caucasian and AfricanAmerican subjects and their impact on the metabolism of 7-ethyl-10-hydroxycamptothecin and flavopiridol anticancer drugs

Abstract

In vitro metabolic studies revealed that along with UDP-glucu-ronosyltransferase (UGT) 1A1, the hepatic UGT1A9 and the extrahepatic UGT1A7 are involved in the biotransformation of the active and toxic metabolite of irinotecan, 7-ethyl-10-hy-droxycamptothecin (SN-38). Variant UGT1A1 and UGT1A7 al-leles have been reported but the polymorphic nature of the UGT1A9 gene has not been revealed yet. To further clarify the molecular determinants of irinotecan-induced toxicity, we have identified and characterized the functionality of novel UGT1A9 polymorphisms and determined whether additional missense polymorphisms exist in UGT1A7. Using direct DNA sequencing, four single nucleotide polymorphisms (SNPs) were identified in the first exons of UGT1A7 and UGT1A9. One of the two amino acid substitutions found in the UGT1A9 gene, UGT1A9*