title: Known and novel sources of variability in the nicotine metabolite ratio in a large sample of treatment-seeking smokers.
abstract: BACKGROUND
  The ratio of 3'hydroxycotinine to cotinine, or nicotine metabolite ratio (NMR), is strongly associated with CYP2A6 genotype, CYP2A6-mediated nicotine and cotinine metabolism, and nicotine clearance. Higher NMR (faster nicotine clearance) is associated retrospectively with heavier smoking and lower cessation rates.
  
  
  METHODS
  NMR as a predictive biomarker of cessation outcomes is being investigated (NCT01314001). In addition to strong CYP2A6 genetic influences on NMR, demographic and hormonal factors alter NMR. Here, we analyzed, for the first time together, these sources of variation on NMR in smokers screened for this clinical trial (N = 1,672).
  
  
  RESULTS
  Participants (mean age = 45.9) were 65.1% Caucasian, 34.9% African American, and 54.8% male. Mean NMR (SD) was higher in Caucasians versus African Americans [0.41 (0.20) vs. 0.33 (0.21); P < 0.001], and in females versus males [0.41 (0.22) vs. 0.37 (0.20); P < 0.001]. Among females, birth control pill use (N = 17) and hormone replacement therapy (N = 14) were associated with 19.5% (P = 0.09) and 29.3% (P = 0.06) higher mean NMR, respectively, albeit nonsignificantly. BMI was negatively associated with NMR (Rho = -0.14; P < 0.001), whereas alcohol use (Rho = 0.11; P < 0.001) and cigarette consumption (Rho = 0.12; P < 0.001) were positively associated with NMR. NMR was 16% lower in mentholated cigarette users (P < 0.001). When analyzed together in a linear regression model, these predictors (each ≤2%) accounted for <8% of total NMR variation.
  
  
  CONCLUSIONS
  Although these factors significantly affected NMR, they contributed little (together <8%; each ≤2%) to total NMR variation.
  
  
  CONCLUSIONS
  Thus, when using NMR, for example, to prospectively guide smoking cessation therapy, these sources of variation are unlikely to cause NMR misclassification.
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, Ontario, Canada. Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Meghan J
authors.initials: MJ
authors.lastname: Chenoweth
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, Ontario, Canada. Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Maria
authors.initials: M
authors.lastname: Novalen
authors.affiliation: Department of Psychology and Center for Children and Families, University at Buffalo, SUNY, Buffalo, New York.
authors.forename: Larry W
authors.initials: LW
authors.lastname: Hawk
authors.affiliation: Department of Psychiatry, Center for Interdisciplinary Research on Nicotine Addiction, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Schnoll
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, Ontario, Canada. Division of Brain and Therapeutics, Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada. Schizophrenia Division, Centre for Addiction and Mental Health (CAMH), Toronto, Ontario, Canada.
authors.forename: Tony P
authors.initials: TP
authors.lastname: George
authors.affiliation: Department of Behavioral Science, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Cinciripini
authors.affiliation: Department of Psychiatry, Center for Interdisciplinary Research on Nicotine Addiction, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Caryn
authors.initials: C
authors.lastname: Lerman
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, Ontario, Canada. Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada. Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada. r.tyndale@utoronto.ca.
authors.forename: Rachel F
authors.initials: RF
authors.lastname: Tyndale
mesh_terms: D003367:Cotinine / Q000031:analogs & derivatives* / Q000097:blood*; D065637:Cytochrome P-450 CYP2A6 / Q000235:genetics / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D009538:Nicotine / Q000378:metabolism*; D011237:Predictive Value of Tests; D012907:Smoking / Q000097:blood* / Q000235:genetics; D016540:Smoking Cessation; D014029:Tobacco Use Disorder / Q000201:enzymology / Q000208:ethnology / Q000235:genetics / Q000378:metabolism*
chemical_list: C001381:hydroxycotinine; D009538:Nicotine; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6; D003367:Cotinine