Abstract 918: Glucuronidation genotypes and nicotine metabolic phenotypes: Importance of UGT2B10 and UGT2B17 knock-out polymorphisms

Abstract

Glucuronidation is an important pathway in the metabolism of nicotine, with ∼28% of urinary nicotine metabolites in the form of glucuronidated compounds. Recent in vitro studies have suggested that the UGTs 2B10 and 2B17 play major roles in nicotine glucuronidation with polymorphisms in both enzymes shown to significantly alter the levels of nicotine-, cotinine-, and trans-3-hydroxy-cotinine (3HC)-glucuronides in human liver microsomes in vitro. In the present study, the relationship between the levels of urinary nicotine metabolites and functional polymorphisms in UGTs 2B10 and 2B17 were analyzed in urine specimens from 104 Caucasian smokers. The levels of nicotine-glucuronide and cotinine-glucuronide were 47 (p<0.0005) and 47% (p<0.0001) lower, respectively, in urine from smokers exhibiting the UGT2B10 (*1/*2) genotype, and 98 (p<0.0001) and 99 (p<0.0001), respectively, in urine from smokers with the UGT2B10 (*2/*2) genotype, as compared to the urinary levels in wild-type UGT2B10 smokers. The levels of 3HC-glucuronide was 64% (p<0.0001) lower in the urine from smokers exhibiting the homozygous UGT2B17 (*2/*2) deletion genotype as compared to the levels in urine from wild-type UGT2B17 subjects. These data are consistent with previous in vitro studies and demonstrate that UGTs 2B10 and 2B17 play important roles in the glucuronidation of nicotine, cotinine and 3HC in vivo, and suggest the UGT2B10 codon 67 SNP and the UGT2B17 deletion significantly reduce overall glucuronidation rates of nicotine and its major metabolites in smokers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 918.

Nicotine-N′-Oxidation by Flavin Monooxygenase Enzymes

“…This study is, to our knowledge, the most comprehensive study examining nicotine-N 0 -oxidation by the FMO family of enzymes. Nicotine-N 0 -oxidation is one of the direct detoxification pathways for nicotine, and while it accounts for a mean of 4%-7% of total urinary nicotine metabolites across multiple studies (16,17), data from this study demonstrate that NOX formation may be a critical pathway for nicotine elimination in people with diminished or deficient CYP2A6 activity. Furthermore, results from this study suggest that functional SNPs in FMOs 1, 2, and 3 may play an important role in nicotine metabolism variability in people with diminished or deficient CYP2A6 activity.…”

“…The Shanghai cohort subjects smoked an average of 15.3 cigarettes/day for 46.5 years as compared with 17.2 cigarettes/day and 31.7 years for the Singapore cohort subjects. In addition to nicotine, eight of its major metabolites (NOX, cotinine-N-oxide, trans-3-hydroxycotinine, nicotine-Nglucuronide, cotinine-N-glucuronide, trans-3 0 -hydroxycotinine-O-glucuronide, and 4-hydroxy-4-(3-pyridyl)-butanoid acid) were quantified in urine samples of the 106 smokers using a previously reported LC/MS method (17).…”

“…It has been reported that FMOs are the enzymes responsible for the stereoselective N 0 -oxidation of nicotine (15). Nicotine-N 0oxide (NOX) formation accounts for 4%-7% of total urinary nicotine metabolites in humans under normal circumstances (16,17). In a small study of 5 subjects, when the CYP2A6mediated hydroxylation pathway is diminished or impaired, urinary levels of NOX are increased to up to 31% of total nicotine metabolites (18).…”

CYP2C19 Plays a Major Role in the HepaticN-Oxidation of Cotinine

“…COT is slowly eliminated from plasma with a half-life of 10-27 h (Jarvis et al, 1988), undergoing metabolism by hydroxylation to 3-hydroxy-COT (3HC) (Miki et al, 1996) and N-(hydroxyl-methyl) norcotinine (Brown et al, 2005), glucuronidation to cotinine-Nglucuronide (COT-Gluc) (Chen et al, 2007), and oxidation to COT-N-oxide (COX), accounting for an average of 63, 4, 24, and 9% of cotinine metabolites, respectively, in the urine of Caucasian smokers (Figure 1) (Rangiah et al, 2011). While extensive studies have been performed examining the enzymes responsible for the formation of COT (Miki et al, 1996), N-(hydroxymethyl)-norcotinine (Brown et al, 2005), and COT-Gluc (Chen et al, 2010), no studies have identified the enzymes responsible for COX formation (Yamanaka et al, 2004;Yildiz, 2004).…”