Interindividual Variability in Nicotine Metabolism: C-Oxidation and Glucuronidation

Abstract

Summary: Nicotine has roles in the addiction to smoking, replacement therapy for smoking cessation, as a potential medication for several diseases such as Parkinson's disease, Alzheimer's disease, and ulcerative colitis. The absorbed nicotine is rapidly and extensively metabolized and eliminated to urine. A major pathway of nicotine metabolism is C-oxidation to cotinine, which is catalyzed by CYP2A6 in human livers. Cotinine is subsequently metabolized to trans-3?-hydroxycotinine by CYP2A6. Nicotine and cotinine are glucuronidated to N-glucuronides mainly by UGT1A4 and partly by UGT1A9. Trans-3?-hydroxycotinine is glucuronidated to O-glucuronide mainly by UGT2B7 and partly by UGT1A9. Approximately 90z of the total nicotine uptake is eliminated as these metabolites and nicotine itself. The nicotine metabolism is an important determinant of the clearance of nicotine. Recently, advances in the understanding of the interindividual variability in nicotine metabolism have been made. There are substantial data suggesting that the large interindividual diŠerences in cotinine formation are associated with genetic polymorphisms of the CYP2A6 gene. Interethnic diŠerences have also been observed in the cotinine formation and the allele frequencies of the CYP2A6 alleles. Since the genetic polymorphisms of the CYP2A6 gene have a major impact on nicotine clearance, its relationships with smoking behavior or the risk of lung cancer have been suggested. The metabolic pathways of the glucuronidation of nicotine, cotinine, and trans-3?-hydroxycotinine in humans would be one of the causal factors for the interindividual diŠerences in nicotine metabolism. This review mainly summarizes recent results from our studies.

Polymorphism of Cytochrome P450 2a6 (Cyp2a6*1 and Cyp2a6*4) Among Javanese Indonesian Smoker and Non Smoker

“…Two CYP2A6 alleles (CYP2A6*1 (wild type allele) and CYP2A6*4 were identified in the Javanese subjects used in the study. The selection of variant alleles for genotyping was based on functional importance and occurance frequency in Asian (Nakajima and Yokoi, 2005;Oscarson, 2001).…”

“…There are 80 numbered CYP2A6 allelic variants identified to date, however, not all have been functionally characterized (www.cypalleles.ki.se/cyp2a6.htm). Among 80 CYP2A6 allelic variants, CYP2A6*4 presents a whole gene deletion (Oscarson et al, 1999), that accounts for the majority of poor metabolizer (PM) in Asian populations (Nakajima and Yokoi, 2005;Oscarson, 2001).…”

Human UDP-Glucuronosyltransferase (UGT) 2B10: Validation of Cotinine as a Selective Probe Substrate, Inhibition by UGT Enzyme-Selective Inhibitors and Antidepressant and Antipsychotic Drugs, and Structural Determinants of Enzyme Inhibition

“…The mean K m (2.78 mM) and V max (297 pmol/mg.min) values for human liver microsomal cotinine N-glucuronidation determined in this study tended to be higher and lower, respectively, than previously reported values. The reasons for this are unclear, although 89-fold variability in the rates of nicotine N-glucuronidation has been observed in a panel of microsomes from 14 livers (Nakajima and Yokoi, 2005). The commercially sourced HLM employed in this study were a pool from 150 donors (equal numbers of males and females), whereas most reports have generally used microsomes from fewer donors (Ghosheh and Hawes, 2002;Nakajima et al, 2002;Kaivosaari et al, 2007).…”

Overview of the pharmacogenomics of cigarette smoking

“…173 CYP2A6 is located on chromosome 19 (19q13.2) and a nearby region was associated with smoking frequency (X1 cigarette per day) in a genome-wide linkage scan. 39 Large interindividual and interethnic variations in CYP2A6 activity have been reported; [170][171][172][174][175][176][177] this variability is mainly attributed to the large genetic variations in CYP2A6. 178,179 A brief summary of how genetic variations in CYP2A6 affect smoking behaviors will be provided here as a detailed review was recently published.…”