This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Malaiyandi, V. Articles by Tyndale, R. F. Search for Related Content PubMed PubMed Citation Articles by Malaiyandi, V. Articles by Tyndale, R. F. Related Collections Epidemiology Epidemiology: Biomarkers

CYP2A6 Genotype, Phenotype, and the Use of Nicotine Metabolites as Biomarkers during Ad libitum Smoking

¹ Department of Pharmacology, Centre for Addiction and Mental Health, University of Toronto and ² Ventana Clinical Research, Toronto, Ontario, Canada

Requests for reprints: Rachel F. Tyndale, Department of Pharmacology, University of Toronto, Medical Sciences Building, Room 4336, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8. Phone: 416-978-6374; Fax: 416-978-6395. E-mail: r.tyndale{at}utoronto.ca

CYP2A6 inactivates nicotine to cotinine and cotinine to 3-hydroxycotinine. We investigated which of plasma nicotine and metabolites were most related to CYP2A6 genotype and smoking levels. We assessed demographic and smoking histories in 152 Caucasian ad libitum smokers, measured breath carbon monoxide (CO) levels, and determined plasma nicotine, cotinine, and 3-hydroxycotinine by high-performance liquid chromatography and CYP2A6 genotypes by PCR. Cigarettes per day was most closely related to CO (r = 0.60, P < 0.001) followed by plasma cotinine (r = 0.53, P < 0.001), whereas plasma cotinine was most strongly correlated with CO levels (r = 0.74, P < 0.001), confirming that cotinine is a good indicator of smoking levels; this was not limited by CYP2A6 variants. 3-Hydroxycotinine/cotinine is reported to be a good marker of CYP2A6 activity, and we found that the 3-hydroxycotinine/(cotinine + nicotine) ratio was most correlated with CYP2A6 genotype (r = 0.38, P < 0.001). Inclusion of the CYP2A6*12A allele strengthened the correlation (r = 0.46, P < 0.001), suggesting that the identification of novel alleles will continue to improve this relationship. Nicotine metabolism is slower in smokers, and we have shown that CYP2A6 is reduced by nicotine treatment in monkeys. Here, we found that plasma nicotine levels were inversely correlated with CYP2A6 activity (3-hydroxycotinine/cotinine, r = –0.41, P < 0.001) among those without CYP2A6 variants, suggesting a reduction in metabolism with higher nicotine levels. Together, these findings (a) confirm the use of plasma cotinine and CO as indicators of Caucasians' smoking levels, and that this is not limited by CYP2A6 genetic variation; (b) indicate that 3-hydroxycotinine/cotinine and 3-hydroxycotinine/(cotinine + nicotine) are moderately good indicators of the CYP2A6 genotype; and (c) support that nicotine exposure may reduce its own metabolism. (Cancer Epidemiol Biomarkers Prev 2006;15(10):1812–9)

This article has been cited by other articles:

				M. E. Mooney, Z.-z. Li, S. E. Murphy, P. R. Pentel, C. Le, and D. K. Hatsukami Stability of the Nicotine Metabolite Ratio in ad Libitum and Reducing Smokers Cancer Epidemiol. Biomarkers Prev., June 1, 2008; 17(6): 1396 - 1400. [Abstract] [Full Text] [PDF]

				G. E. Swan and C. N. Lessov-Schlaggar The Genetics of Nicotine Addiction: Current Status and Future Directions ASCO Educational Book, January 1, 2008; 2008(1): 70 - 73. [Abstract] [Full Text] [PDF]