Nicotine Metabolism and Smoking: Ethnic Differences in the Role of P450 2A6

Abstract

Nicotine is the primary addictive agent in tobacco, and P450 2A6 (gene name: CYP2A6) is the primary catalyst of nicotine metabolism. It was proposed more than 20 years ago that individuals who metabolize nicotine poorly would smoke less, either fewer cigarettes per day or less intensely per cigarette, compared to smokers who metabolize nicotine more efficiently. These poor metabolizers would then be less likely to develop lung cancer due to their lower exposure to the many carcinogens delivered with nicotine in each puff of smoke. Numerous studies have reported that smokers who carry reduced activity or null CYP2A6 alleles do smoke less. Yet only in Asian populations, both Japanese and Chinese, which have a high prevalence of genetic variants, has a link between CYP2A6, smoking dose, and lung cancer been established. In other ethnic groups, it has been challenging to confirm a direct link between P450 2A6-mediated nicotine metabolism and the risk of lung cancer. This challenge is due in part to the difficulty in accurately quantifying smoking dose and accurately predicting or measuring P450 2A6-mediated nicotine metabolism. Biomarkers of nicotine metabolism and smoking exposure, including the ratio of trans-3-hydroxycotine to cotinine, a measure of P450 2A6 activity and plasma cotinine, or urinary total nicotine equivalents (the sum of nicotine and six metabolites) as measures of exposure are useful for addressing this challenge. However, to take full advantage of these biomarkers in the study of ethnic/racial differences in the risk of lung cancer requires the complete characterization of nicotine metabolism across ethnic/racial groups. Variation in metabolism pathways, other than those catalyzed by P450 2A6, can impact biomarkers of both nicotine metabolism and dose. This is clearly important for smokers with low levels of UGT2B10-catalyzed nicotine and cotinine glucuronidation because the UGT2B10 genotype influences plasma cotinine levels. Cotinine is not glucuronidated in 15% of African American smokers (compared to 1% of Whites) due to the prevalence of a UGT2B10 splice variant. This variant contributes significantly to the higher plasma cotinine levels per cigarette in this group and may also influence the accuracy of the 3HCOT to cotinine ratio as a measure of P450 2A6 activity.

Figure 1.

Nicotine metabolic pathways. Adapted from Murphy et al, Carcinogenesis (2014) 35

Figure 2.

Proportion of nicotine metabolized by C-oxidation, N-glucuronidation and N-oxidation in five ethnic/racial groups (n=2239 from a subset of the Multiethnic Cohort). The values are the molar percent of nicotine and six metabolites excreted in urine, and each slice of the pie is the mean percentage of the compound relative to TNE. From Murphy et al, Carcinogenesis (2014) 35 (11): 2526–2533. Used by permission of Oxford University Press.

Figure 3.

TNE by CYP2A6 diplotype. Diplotypes categories are defined by the functional activity of each allele as follows: N (no variant allele or *1A +*14); I (intermediate activity), *1H, *1A, *9, *17, *23; L (little or no activity), *4, *1A+2, *1H+2, *12, *1H+*7, *7. Alleles as described http://www.cypalleles.ki.se/cyp2a6.htm. From Murphy et al, Carcinogenesis (2016) 37 (3): 269–279. Used by permission of Oxford University Press.