CYP2A6 and CYP2B6 genetic variation and its association with nicotine metabolism in South Western Alaska Native people

Abstract

Objectives Alaska Native people (AN) have a high prevalence of tobacco use and associated morbidity and mortality when compared to the general U.S. population. Variation in the CYP2A6 and CYP2B6 genes, encoding enzymes responsible for nicotine metabolic inactivation and procarcinogen activation, has not been characterized in AN and may contribute to the increased risk. Methods AN people (n = 400) residing in the Bristol Bay region of South Western Alaska were recruited for a cross-sectional study on tobacco use. They were genotyped for CYP2A6*1X2A, *1X2B, *1B, *2, *4, *7, *8, *9, *10, *12, *17, *35 and CYP2B6*4, *6, *9 and provided plasma and urine samples for measurement of nicotine and metabolites. Results CYP2A6 and CYP2B6 variant frequencies among the AN Yupik people (n=361) were significantly different from other ethnicities. Nicotine metabolism (as measured by the plasma and urinary ratio of metabolites trans-3’hydroxycotinine to cotinine [(3HC/COT)] was significantly associated with CYP2A6 (P< 0.001) but not CYP2B6 genotype (P = 0.95) when controlling for known covariates. Of note, plasma 3HC/COT ratios were high in the entire Yupik people, and among the Yupik CYP2A6 wild-type participants they were substantially higher than previously characterized racial/ethnic groups (P < 0.001 vs. Caucasians and African Americans). Conclusions Yupik AN people have a unique CYP2A6 genetic profile which associated strongly with in vivo nicotine metabolism. More rapid CYP2A6-mediated nicotine and nitrosamine metabolism in the Yupik people may modulate tobacco-related disease risk.

The relationship between the nicotine metabolite ratio and three self-report measures of nicotine dependence across sex and race

“…Helen et al, 2012), Caucasians were more likely to be normal metabolizers of nicotine, compared to African Americans. These findings are consistent with previous studies showing that the frequency of CYP2A6 alleles, which influence variability in nicotine metabolism, vary across racial/ethnic groups (Binnington et al, 2012; Nakajima et al, 2006). Likewise, the present study showed that women and African Americans report higher levels of nicotine dependence, however this result was confined to the use of the TTFC measure of nicotine dependence.…”

High tobacco use prevalence with significant regional and sex differences in smokeless tobacco use among Western Alaska Native people: the WATCH study

“…Research has demonstrated that dual- and multi-product tobacco users experience lower cessation rates [17,18], possibly due to greater cotinine and dependence levels [50]. On average, AN smokers living in Bristol Bay smoke about half as many cigarettes (7.8) per day [42] as US smokers (14.2) [51], but demonstrate similar plasma cotinine levels (170 ng/mL and 200 ng/mL, respectively), suggesting altered nicotine metabolism [49,52]. These changes in nicotine pharmacokinetics imply the need for a increased dosing of nicotine replacement therapy to aid in smoking cessation, a need that may extend to other AN populations, such as those in the Y-K or Norton Sound regions.…”

Characterization of CYP2B6 in a CYP2B6-Humanized Mouse Model: Inducibility in the Liver by Phenobarbital and Dexamethasone and Role in Nicotine Metabolism In Vivo

“…The contribution of CYP2B6 to nicotine clearance in humans is believed to be relatively small and influenced by the activity of the more dominant CYP2A6 (Yamanaka et al, 2004;Dicke et al, 2005;Al Koudsi and Tyndale, 2010). The impact of CYP2B6 genetic polymorphisms on nicotine clearance has been examined in a number of studies, yielding positive results in some (Johnstone et al, 2006;Ring et al, 2007;Bloom et al, 2013), but not in others (Lee et al, 2007;Binnington et al, 2012). Here, we have provided in vivo proof-ofprinciple in the mouse model that CYP2B6 could make a significant contribution to nicotine oxidation and systemic clearance, particularly at the induced level, albeit in the absence of the more dominant mouse CYP2A5 and CYP2B enzymes.…”