curonidation Genotypes and Nicotine Metabolic notypes: Importance of Functional UGT2B10 and R 2B17 Polymorphisms

ownloade curonidation is an important pathway in the metabolism of nicotine, with previous studies suggesting 22% of urinary nicotine metabolites are in the form of glucuronidated compounds. Recent in vitro studve suggested that the UDP-glucuronosyltransferases (UGT) 2B10 and 2B17 play major roles in nicotine onidation with polymorphisms in both enzymes shown to significantly alter the levels of nicotineonide, cotinine-glucuronide, and trans-3′-hydroxycotinine (3HC)–glucuronide in human liver microin vitro. In the present study, the relationship between the levels of urinary nicotine metabolites and onal polymorphisms in UGTs 2B10 and 2B17 was analyzed in urine specimens from 104 Caucasian rs. Based on their percentage of total urinary nicotine metabolites, the levels of nicotine-glucuronide tinine-glucuronide were 42% (P < 0.0005) and 48% (P < 0.0001), respectively, lower in the urine from rs exhibiting the UGT2B10 (*1/*2) genotype and 95% (P < 0.05) and 98% (P < 0.05), respectively, lower in ine from smokers with the UGT2B10 (*2/*2) genotype compared with the urinary levels in smokers the wild-type UGT2B10 (*1/*1) genotype. The level of 3HC-glucuronide was 42% (P < 0.001) lower in ine from smokers exhibiting the homozygous UGT2B17 (*2/*2) deletion genotype compared with els in urine from wild-type UGT2B17 subjects. These data suggest that UGTs 2B10 and 2B17 play imt roles in the glucuronidation of nicotine, cotinine, and 3HC and suggest that the UGT2B10 codon 67 portan SNP and the UGT2B17 gene deletion significantly reduce overall glucuronidation rates of nicotine and its major metabolites in smokers. Cancer Res; 70(19); 7543–52. ©2010 AACR.