Determination of CYP2A6 Activity in the US Population by Use of a Caffeine Metabolite Ratio in Spot Urine Samples: NHANES 2009–2010

Abstract

Cytochrome P450 enzyme CYP2A6 is a phase I enzyme expressed primarily in the liver, accounting for approximately 4% of all P450 content. CYP2A6 plays a role in the metabolism of caffeine, nicotine, and several drugs used in the treatment of cancer and infectious diseases. CYP2A6 polymorphisms give rise to inter‐individual differences in CYP2A6 activity, and these differences can be further influenced by dietary and lifestyle factors. Lower CYP2A6 activity has been associated with a reduced risk of various cancers, and differences in CYP2A6 activity can influence smoking behavior and likelihood of cessation. Caffeine metabolite ratios (MR) have been developed to assess CYP2A6 activity, and the urine MR of 1,7‐dimethyluric acid (17U) to paraxanthine (17X) (i.e., 17U/17X) has been used to determine CYP2A6 activity. Additionally, the MR of 17U to 1‐methylxanthine (1X) (i.e., 17U/1X) has shown promise in less controlled settings where regular dietary caffeine intake and spot urine samples were used. In this study we described CYP2A6 activity in the US population ≥6 y by selected demographic, lifestyle and physiologic variables. We used spot urine molar concentrations of 17U and 1X from the cross‐sectional NHANES 2009–2010 to calculate CYP2A6 activity by use of the MR 17U/1X. We excluded the individuals with evidence of insufficient caffeine exposure to reliably calculate the CYP2A6 MR and subjects taking prescription medications known to interfere with caffeine metabolism. We performed bivariate comparisons of unadjusted geometric mean (GM) CYP2A6 MR for categorical variables (n=2197), and used Spearman correlation to examine the relation of CYP2A6 MR with continuous variables. CYP2A6 activity was higher in females vs. males (Wald F P <0.0001), highest in Hispanics, followed by non‐Hispanic whites and lowest in non‐Hispanic blacks (Wald F P <0.0001), and increased with age (Spearman ρ = 0.41, P <0.001). CYP2A6 MR was higher in individuals with evidence of inflammation (serum CRP ≥5 mg/L vs. <5 mg/L; Wald F P <0.0001), diabetes (yes vs. no based on a physician's diagnosis; Wald F P = 0.0025), and impaired kidney function (CKD 3–5 vs. CKD 1–2 and normal; Wald F P <0.0001). CYP2A6 MR was lower in smokers vs. non‐smokers (serum cotinine ≤10 ng/mL vs. >10 ng/mL; Wald F P <0.0001). CYP2A6 activity was positively associated with BMI (Spearman ρ = 0.36, P <0.0001) and was negatively associated with leisure physical activity (Spearman ρ = −0.15, P = 0.0003). The associations that we observed for CYP2A6 activity with age, sex, and race‐ethnicity, smoking status, inflammation, and physical activity were generally consistent with observations from other studies. We believe that our study is the first to report estimates of CYP2A6 activity obtained from spot urine MRs in a representative sample of the US population.