Variation in trans-3'-hydroxycotinine glucuronidation does not alter the nicotine metabolite ratio or nicotine intake.
BACKGROUND
CYP2A6 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.


METHODS
Plasma 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.


RESULTS
The 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.


CONCLUSIONS
Variation 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.
Department Pharmacology and Toxicology, University of Toronto, Ontario, Canada.
Andy Z X
AZ
Zhu
Qian
Q
Zhou
Lisa Sanderson
LS
Cox
Jasjit S
JS
Ahluwalia
Neal L
NL
Benowitz
Rachel F
RF
Tyndale
D000293:Adolescent; D000328:Adult; D001741:Black or African American; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D015415:Biomarkers / Q000097:blood / Q000652:urine; D003367:Cotinine / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism; D065637:Cytochrome P-450 CYP2A6; D005260:Female; D017353:Gene Deletion; D005838:Genotype; D020719:Glucuronides / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens; D009538:Nicotine / Q000032:analysis* / Q000378:metabolism; D012907:Smoking; D055815:Young Adult
D015415:Biomarkers; D020719:Glucuronides; D015778:Minor Histocompatibility Antigens; C001381:hydroxycotinine; D009538:Nicotine; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6; C552162:UGT2B10 protein, human; D014453:Glucuronosyltransferase; C500513:UGT2B17 protein, human; D003367:Cotinine