Effect of UGT2B10, UGT2B17, FMO3, and OCT2 genetic variation on nicotine and cotinine pharmacokinetics and smoking in African Americans.
Nicotine metabolism rates differ considerably among individuals, even after controlling for variation in the major nicotine-metabolizing enzyme, CYP2A6. In this study, the impact of genetic variation in alternative metabolic enzymes and transporters on nicotine and cotinine (COT) pharmacokinetics and smoking was investigated.



We examined the impact of UGT2B10, UGT2B17, FMO3, NAT1, and OCT2 variation on pharmacokinetics and smoking (total nicotine equivalents and topography) before and after stratifying by CYP2A6 genotype in 60 African American (AA) smokers who received a simultaneous intravenous infusion of deuterium-labeled nicotine and COT.



Variants in UGT2B10 and UGT2B17 were associated with urinary glucuronidation ratios (glucuronide/free substrate). UGT2B10 rs116294140 was associated with significant alterations in COT and modest alterations in nicotine pharmacokinetics. These alterations, however, were not sufficient to change nicotine intake or topography. Neither UGT2B10 rs61750900, UGT2B17*2, FMO3 rs2266782, nor NAT1 rs13253389 altered nicotine or COT pharmacokinetics among all individuals (n=60) or among individuals with reduced CYP2A6 activity (n=23). The organic cation transporter OCT2 rs316019 significantly increased nicotine and COT Cmax (P=0.005, 0.02, respectively) and decreased nicotine clearance (P=0.05). UGT2B10 rs116294140 had no significant impact on the plasma or urinary trans-3'-hydroxycotinine/COT ratio, commonly used as a biomarker of CYP2A6 activity.



We found that polymorphisms in genes other than CYP2A6 represent minor sources of variation in nicotine pharmacokinetics, insufficient to alter smoking in AAs. The change in COT pharmacokinetics with UGT2B10 rs116294140 highlights the UGT2B10 gene as a source of variability in COT as a biomarker of tobacco exposure among AA smokers.
Departments of aPharmacology and Toxicology bPsychiatry, University of Toronto cDepartment of Molecular Brain Science, Centre for Addiction and Mental Health, Campbell Family Mental Health Research Institute, Toronto, Ontario, Canada dDepartments of Medicine and Biopharmaceutical Sciences, Division of Clinical Pharmacology and Experimental Therapeutics, Medical Services eCenter for Tobacco Control Research and Education, University of California, San Francisco, California, USA.
Taraneh
T
Taghavi
Gideon
G
St Helen
Neal L
NL
Benowitz
Rachel F
RF
Tyndale
D061605:Administration, Intravenous; D001741:Black or African American / Q000235:genetics*; D003367:Cotinine / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D015778:Minor Histocompatibility Antigens / Q000235:genetics; D006899:Mixed Function Oxygenases / Q000235:genetics*; D009538:Nicotine / Q000008:administration & dosage* / Q000493:pharmacokinetics; D027701:Organic Cation Transport Proteins / Q000235:genetics*; D000075102:Organic Cation Transporter 2; D000071184:Pharmacogenomic Variants; D020641:Polymorphism, Single Nucleotide; D012907:Smoking / Q000009:adverse effects / Q000235:genetics
D015778:Minor Histocompatibility Antigens; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; C491013:SLC22A2 protein, human; D009538:Nicotine; D006899:Mixed Function Oxygenases; C552162:UGT2B10 protein, human; D014453:Glucuronosyltransferase; C500513:UGT2B17 protein, human; D003367:Cotinine