The ability of plasma cotinine to predict nicotine and carcinogen exposure is altered by differences in CYP2A6: the influence of genetics, race, and sex.
BACKGROUND
Cotinine, a nicotine metabolite, is a biomarker of tobacco, nicotine, and carcinogen exposure. However, a given cotinine level may not represent the same tobacco exposure; for example, African-Americans have higher cotinine levels than Caucasians after controlling for exposure.


METHODS
Cotinine levels are determined by the amount of cotinine formation and the rate of cotinine removal, which are both mediated by the enzyme CYP2A6. Because CYP2A6 activity differs by sex (estrogen induces CYP2A6) and genotype, their effect on cotinine formation and removal was measured in nonsmoking Caucasians (Study 1, n = 181) infused with labeled nicotine and cotinine. The findings were then extended to ad libitum smokers (Study 2, n = 163).


RESULTS
Study 1: Reduced CYP2A6 activity altered cotinine formation less than cotinine removal resulting in ratios of formation to removal of 1.31 and 1.12 in CYP2A6 reduced and normal metabolizers (P = 0.01), or 1.39 and 1.12 in males and females (P = 0.001), suggesting an overestimation of tobacco exposure in slower metabolizers. Study 2: Cotinine again overestimated tobacco and carcinogen exposure by 25% or more in CYP2A6 reduced metabolizers (≈2-fold between some genotypes) and in males.


CONCLUSIONS
In people with slower relative to faster CYP2A6 activity, cotinine accumulates resulting in substantial differences in cotinine levels for a given tobacco exposure.


CONCLUSIONS
Cotinine levels may be misleading when comparing those with differing CYP2A6 genotypes within a race, between races with differing frequencies of CYP2A6 gene variants (i.e., African-Americans have higher frequencies of reduced function variants contributing to their higher cotinine levels), or between the sexes.
Departments of Psychiatry, Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
Andy Z X
AZ
Zhu
Caroline C
CC
Renner
Dorothy K
DK
Hatsukami
Gary E
GE
Swan
Caryn
C
Lerman
Neal L
NL
Benowitz
Rachel F
RF
Tyndale
D001741:Black or African American / Q000235:genetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D015415:Biomarkers / Q000032:analysis; D002273:Carcinogens / Q000494:pharmacology*; D003367:Cotinine / Q000097:blood*; D003430:Cross-Sectional Studies; D065637:Cytochrome P-450 CYP2A6; D005260:Female; D005500:Follow-Up Studies; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008297:Male; D009538:Nicotine / Q000009:adverse effects*; D018722:Nicotinic Agonists / Q000009:adverse effects; D011379:Prognosis; D012737:Sex Factors; D012907:Smoking / Q000009:adverse effects / Q000208:ethnology / Q000235:genetics; D018433:Twin Studies as Topic; D044465:White People / Q000235:genetics*
D015415:Biomarkers; D002273:Carcinogens; D018722:Nicotinic Agonists; D009538:Nicotine; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6; D003367:Cotinine