Glucuronidation genotypes and nicotine metabolic phenotypes: importance of functional UGT2B10 and UGT2B17 polymorphisms.

Glucuronidation is an important pathway in the metabolism of nicotine, with previous studies suggesting that ∼22% of urinary nicotine metabolites are in the form of glucuronidated compounds. Recent in vitro studies have suggested that the UDP-glucuronosyltransferases (UGT) 2B10 and 2B17 play major roles in nicotine glucuronidation with polymorphisms in both enzymes shown to significantly alter the levels of nicotine-glucuronide, cotinine-glucuronide, and trans-3'-hydroxycotinine (3HC)-glucuronide in human liver microsomes in vitro. In the present study, the relationship between the levels of urinary nicotine metabolites and functional polymorphisms in UGTs 2B10 and 2B17 was analyzed in urine specimens from 104 Caucasian smokers. Based on their percentage of total urinary nicotine metabolites, the levels of nicotine-glucuronide and cotinine-glucuronide were 42% (P < 0.0005) and 48% (P < 0.0001), respectively, lower in the urine from smokers exhibiting the UGT2B10 (*1/*2) genotype and 95% (P < 0.05) and 98% (P < 0.05), respectively, lower in the urine from smokers with the UGT2B10 (*2/*2) genotype compared with the urinary levels in smokers having the wild-type UGT2B10 (*1/*1) genotype. The level of 3HC-glucuronide was 42% (P < 0.001) lower in the urine from smokers exhibiting the homozygous UGT2B17 (*2/*2) deletion genotype compared with the levels in urine from wild-type UGT2B17 subjects. These data suggest that UGTs 2B10 and 2B17 play important roles in the glucuronidation of nicotine, cotinine, and 3HC and suggest that the UGT2B10 codon 67 SNP and the UGT2B17 gene deletion significantly reduce overall glucuronidation rates of nicotine and its major metabolites in smokers.

[1]  D. Hatsukami,et al.  Nicotine Metabolism in African Americans and European Americans: Variation in Glucuronidation by Ethnicity and UGT2B10 Haplotype , 2010, Journal of Pharmacology and Experimental Therapeutics.

[2]  N. Benowitz,et al.  Association of Nicotine Metabolite Ratio and CYP2A6 Genotype With Smoking Cessation Treatment in African‐American Light Smokers , 2009, Clinical pharmacology and therapeutics.

[3]  C. Lerman,et al.  Nicotine metabolic rate predicts successful smoking cessation with transdermal nicotine: A validation study , 2009, Pharmacology Biochemistry and Behavior.

[4]  C. Lerman,et al.  Nicotine Dependence Pharmacogenetics: Role of Genetic Variation in Nicotine-Metabolizing Enzymes , 2009, Journal of neurogenetics.

[5]  L. Epstein,et al.  Toward Personalized Therapy for Smoking Cessation: A Randomized Placebo‐controlled Trial of Bupropion , 2008, Clinical pharmacology and therapeutics.

[6]  P. Gupta,et al.  Tobacco addiction , 2008, The Lancet.

[7]  R. Dellinger,et al.  Identification of a prevalent functional missense polymorphism in the UGT2B10 gene and its association with UGT2B10 inactivation against tobacco-specific nitrosamines , 2008, Pharmacogenetics and genomics.

[8]  R. Tyndale,et al.  A novel CYP2A6 allele, CYP2A6*23, impairs enzyme function in vitro and in vivo and decreases smoking in a population of Black-African descent , 2008, Pharmacogenetics and genomics.

[9]  R. Dellinger,et al.  Glucuronidation of nicotine and cotinine by UGT2B10: loss of function by the UGT2B10 Codon 67 (Asp>Tyr) polymorphism. , 2007, Cancer research.

[10]  M. Finel,et al.  Nicotine Glucuronidation and the Human UDP-Glucuronosyltransferase UGT2B10 , 2007, Molecular Pharmacology.

[11]  A. N. Hicks,et al.  The UDP-Glucuronosyltransferase 2B17 Gene Deletion Polymorphism: Sex-Specific Association with Urinary 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanol Glucuronidation Phenotype and Risk for Lung Cancer , 2007, Cancer Epidemiology Biomarkers & Prevention.

[12]  C. Lerman,et al.  Nicotine metabolite ratio predicts efficacy of transdermal nicotine for smoking cessation , 2006, Clinical pharmacology and therapeutics.

[13]  J. Muscat,et al.  Genotype–phenotype correlation between the polymorphic UGT2B17 gene deletion and NNAL glucuronidation activities in human liver microsomes , 2005, Pharmacogenetics and genomics.

[14]  Neal L. Benowitz,et al.  Metabolism and Disposition Kinetics of Nicotine , 2005, Pharmacological Reviews.

[15]  R. Tyndale,et al.  Implications of CYP2A6 Genetic Variation for Smoking Behaviors and Nicotine Dependence , 2005, Clinical pharmacology and therapeutics.

[16]  M. Nakajima,et al.  TRANS-3′-HYDROXYCOTININE O- AND N-GLUCURONIDATIONS IN HUMAN LIVER MICROSOMES , 2005, Drug Metabolism and Disposition.

[17]  T. A. Bell,et al.  Characterization of a common deletion polymorphism of the UGT2B17 gene linked to UGT2B15. , 2004, Genomics.

[18]  N. Benowitz,et al.  Nicotine metabolite ratio as an index of cytochrome P450 2A6 metabolic activity , 2004, Clinical pharmacology and therapeutics.

[19]  S. Murphy,et al.  N-glucuronidation of trans-3'-hydroxycotinine by human liver microsomes. , 2003, Chemical Research in Toxicology.

[20]  S. Murphy,et al.  N-glucuronidation of nicotine and cotinine by human liver microsomes and heterologously expressed UDP-glucuronosyltransferases. , 2003, Drug metabolism and disposition: the biological fate of chemicals.

[21]  E. Warren,et al.  A Human Minor Histocompatibility Antigen Resulting from Differential Expression due to a Gene Deletion , 2003, The Journal of experimental medicine.

[22]  S. Vashishtha,et al.  Formation of the quaternary ammonium-linked glucuronide of nicotine in human liver microsomes: identification and stereoselectivity in the kinetics. , 2001, Drug metabolism and disposition: the biological fate of chemicals.

[23]  S. Hecht,et al.  Effects of watercress consumption on urinary metabolites of nicotine in smokers. , 1999, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[24]  D. Hatsukami,et al.  Quantitation of 4-oxo-4-(3-pyridyl)butanoic acid and enantiomers of 4-hydroxy-4-(3-pyridyl)butanoic acid in human urine: A substantial pathway of nicotine metabolism. , 1999, Chemical research in toxicology.

[25]  N. Benowitz,et al.  Metabolism of nicotine to cotinine studied by a dual stable isotope method , 1994, Clinical pharmacology and therapeutics.

[26]  W. S. Caldwell,et al.  Direct determination of cotinine-N-glucuronide in urine using thermospray liquid chromatography/mass spectrometry. , 1994, Biological mass spectrometry.

[27]  N. Benowitz,et al.  Nicotine and cotinine elimination pharmacokinetics in smokers and nonsmokers , 1993, Clinical pharmacology and therapeutics.

[28]  P. Crooks,et al.  Characterization of the glucuronide conjugate of cotinine: a previously unidentified major metabolite of nicotine in smokers' urine. , 1992, Chemical research in toxicology.

[29]  N. Benowitz,et al.  Nicotine chemistry, metabolism, kinetics and biomarkers. , 2009, Handbook of experimental pharmacology.

[30]  M. Nishimura,et al.  Tissue-specific mRNA expression profiles of human phase I metabolizing enzymes except for cytochrome P450 and phase II metabolizing enzymes. , 2006, Drug metabolism and pharmacokinetics.

[31]  M. Nakajima,et al.  Interindividual variability in nicotine metabolism: C-oxidation and glucuronidation. , 2005, Drug metabolism and pharmacokinetics.

[32]  W. S. Caldwell,et al.  Determination of Nicotine N-1-Glucuronide, a Quaternary N-Glucuronide Conjugate, in Human Biological Samples , 2000, Drug metabolism and drug interactions.

[33]  A. Lyman.  Tobacco addiction. , 1996, JAMA.

[34]  N. Benowitz,et al.  Nicotine metabolic profile in man: comparison of cigarette smoking and transdermal nicotine. , 1994, The Journal of pharmacology and experimental therapeutics.