Novel Functional Polymorphisms in the UGT1A7 and UGT1A9 Glucuronidating Enzymes in Caucasian and African-American Subjects and Their Impact on the Metabolism of 7-Ethyl-10-hydroxycamptothecin and Flavopiridol Anticancer Drugs

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Abstract
In vitro metabolic studies revealed that along with UDP-glucuronosyltransferase (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-hydroxycamptothecin (SN-38). Variant UGT1A1 and UGT1A7 alleles 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*3 (M33T), results in a dramatic decrease in SN-38 glucuronide formation, with 3.8% of the activity of the UGT1A9*1 allele. In turn, the glucuronidation of flavopiridol, an anticancer drug biotransformed predominantly by UGT1A9, remains unaffected, indicating a substrate-dependent impact of this variant. UGT1A9*3 is detected only in Caucasians and 4.4% of the population tested was found heterozygous (*1/*3). Two additional UGT1A7 SNPs were found exclusively in African-American subjects and generate five alleles (UGT1A7*5 to *9) when combined to the four known SNPs present in UGT1A7*2, *3, and *4. Upon functional analysis with SN-38, five out of nine UGT1A7 allozymes exhibited much lower SN-38 glucuronidation activities compared with UGT1A7*1, all having in common the mutational changes at codons 115 or 208. Results suggest that these low SN-38 glucuronidating alleles may represent additional molecular determinants of irinotecan-induced toxicity and warrant further investigations.