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Abstract
BackgroundCYP2A6 metabolizes nicotine to its primary metabolite cotinine and also mediates the metabolism of cotinine to trans-3′-hydroxycotinine (3HC). The ratio of 3HC to cotinine (the “nicotine metabolite ratio”, NMR) is an in vivo marker for the rate of CYP2A6 mediated nicotine metabolism, and total nicotine clearance, and has been associated with differences in numerous smoking behaviors. The clearance of 3HC, which affects the NMR, occurs via renal excretion and metabolism by UGT2B17, and possibly UGT2B10, to 3HC-glucuronide. We investigated whether slower 3HC glucuronidation alters NMR, altering its ability to predict CYP2A6 activity and reducing its clinical utility.MethodsPlasma NMR, three urinary NMRs, three urinary 3HC glucuronidation phenotypes and total nicotine equivalents were examined in 540 African American smokers. The UGT2B17 gene deletion and UGT2B10*2 were genotyped.ResultsThe UGT2B17 gene deletion, but not UGT2B10*2 genotype, was associated with slower 3HC glucuronidation (indicated by three 3HC-glucuronidation phenotypes), indicating its role in this glucuronidation pathway. However, neither lower rates of 3HC glucuronidation, nor the presence of a UGT2B17 and UGT2B10 reduced function allele, altered plasma or urinary NMRs or levels of smoking.ConclusionsVariation in 3HC glucuronidation activity, including these caused by UGT2B17 gene deletions, did not significantly alter NMR and is therefore unlikely to affect the clinical utility of NMR in smoking behavior and cessation studies. This study demonstrates that NMR is not altered by differences in the rate of 3HC glucuronidation, providing further support that NMR is a reliable indicator of CYP2A6 mediated nicotine metabolism.
Highlights
There are currently more than 1.3 billion tobacco smokers worldwide
No significant difference in baseline demographics, smoking behaviors, baseline plasma cotinine levels, urinary total nicotine equivalents (TNE), and levels of nicotine dependence were observed between UDP-Glucuronosyltransferase 2B17 (UGT2B17) or UGT2B10 genotype groups (Table 1), indicating that neither the UGT2B17 gene deletion nor the UGT2B10*2 were associated with the levels of tobacco consumption or nicotine dependence
The UGT2B17 gene deletion was significantly associated with the secondary 3HC glucuronidation phenotype – the percentage of TNE excreted as 3HC-Gluc (Fig. 1B, P,0.0001)
Summary
There are currently more than 1.3 billion tobacco smokers worldwide. Nicotine is the primary psychoactive tobacco component responsible for tobacco dependence. Cotinine has a much longer half-live compared to 3HC (16 hours vs 5 hours, respectively) [15,16], and at steady state the elimination rate of 3HC is essentially formation-limited. Due to these pharmacokinetic properties, among regular smokers the NMR is generally stable over time and highly reproducible [17,18]. A slow rate of 3HC clearance could increase plasma 3HC levels for a given cotinine level, resulting in a higher NMR compared to those with normal rates of 3HC clearance This effect on NMR is not related to nicotine clearance or CYP2A6 activity and could reduce the clinical utility of NMR. We investigated whether slower 3HC glucuronidation alters NMR, altering its ability to predict CYP2A6 activity and reducing its clinical utility
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