Influence of UGT2B10 Genotype on Urinary Excretion of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol-N-glucuronide by African American Smokers

Abstract

At similar smoking levels African American’s lung cancer risk is as much as twice that of whites. We hypothesized that racial/ethnic differences in UDP-glucuronosyltransferase (UGT)-catalyzed glucuronidation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), a detoxication pathway for the tobacco-specific lung carcinogen NNK (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone), may contribute to this variable risk. UGT2B10 catalyzes NNAL N-glucuronidation and a UGT2B10 splice variant is common among African Americans. Smokers from two independent studies were genotyped for this variant (rs116294140) and an Asp67Tyr variant (rs61750900), and urinary NNAL and NNAL glucuronide concentrations were quantified. In the first, no significant differences in NNAL-N-glucuronidation between African Americans (n=257) and whites (n=354), or between homozygous carriers of UGT2B10 variants (genetic score 2) and non-carriers (score 0) were detected. However, total NNAL glucuronidation by score 2 compared to score 0 smokers was lower (68.9% vs 71.2%, p<0.0001). To more precisely quantify NNAL N-glucuronide in a second study, a sensitive high resolution LC-MS/MS-based method, which separated NNAL, NNAL-O-glucuronide and NNAL-N-glucuronide prior to analysis, was developed. In this study, the excretion of total NNAL (free plus glucuronides) by African American (n=52) and white (n=54) smokers was not different, however, total NNAL glucuronidation by African Americans (64.0%) was slightly less than by whites (68.3%, p=0.05). The mean NNAL N-glucuronidation by African Americans was much lower than for whites (14% vs 24.9%, p<0.00001) but the NNAL O-glucuronidation was greater (50.0% vs 43.3%, p=0.013). UGT2B10 genotype influenced NNAL N-glucuronidation; the geometric mean percentage N-glucuronidation was 22.5% for smokers with genetic score 0 (n=57) and 11.2% for score 2 (n=11). In summary, the high prevalence of a UGT2B10 splice variant among African Americans results in lower NNAL N-glucuronidation but only a small decrease in total NNAL glucuronidation. Therefore despite the significant contribution of UGT2B10 to NNAL-N-glucuronidation, UGT2B10 genotype does not play a large role in NNAL detoxication. Any decrease in N-glucuronidation was accompanied by a parallel increase in O-glucuronidation.

Concentrations of Cotinine and 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanol (NNAL) in U.S. Non-Daily Cigarette Smokers

“…Alternatively, differences may reflect cigarette smoking behavior (e.g., puff number and maximum volume) as well as other individual factors (hormonal, genetics) that modify the cotinine pharmacokinetics parameters. Racial/ethnic differences in nicotine and cotinine glucuronidation (31,32), and to a lesser extent NNAL metabolism (33) have been noted in previous studies. In contrast, NNAL-CR concentrations were similar between NH Blacks and NH Whites.…”

Characterization of the Ontogeny of Hepatic UDP‐Glucuronosyltransferase Enzymes Based on Glucuronidation Activity Measured in Human Liver Microsomes

“…There are no changes in UGT plasticity (induction or suppression) in human hepatic tissue with smoking and alcohol consumption . Alterations of nicotine glucuronidation via UGT2B10 and UGT2B17 was found to be ethnicity‐dependent . Additionally, a study in HLM indicated potential competitive inhibition of morphine metabolism via UGT2B7 and UGT1A3 by alcohol, but this was not through altering enzyme expression per se …”

“…32,33 Alterations of nicotine glucuronidation via UGT2B10 and UGT2B17 was found to be ethnicity-dependent. 34,35 Additionally, a study in HLM indicated potential competitive inhibition of morphine metabolism via UGT2B7 and UGT1A3 by alcohol, but this was not through altering enzyme expression per se. 36 Our results did not demonstrate sex-related differences in the glucuronidation activity in HLMs using a large sample size in either adult or pediatric populations.…”

Effects of a Novel UGT2B Haplotype and UGT1A4*3 Allele Variants on Glucuronidation of Clozapine In vivo

“…However, polymorphisms in the nearest genes, i.e. UGT2B10 and 2B15 have been described to influence the glucuronidation rate of cotinine (nicotine metabolite) and postoperative anxiety after lorazepam premedication, respectively [13,14]. Furthermore, much interests have been paid to the UGT1A4*3 (142 T>G, L48V, MAF = 0.077) allele variant [15], which has been shown to alter the glucuronide formation of various compounds in vitro [15][16][17][18].…”