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

Gang Chen; Nino E Giambrone, Jr; Douglas F Dluzen; Joshua E Muscat; Arthur Berg; Carla J Gallagher; Philip Lazarus

doi:10.1158/0008-5472.CAN-09-4582

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

Journal article

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

Gang Chen, Nino E Giambrone, Jr, Douglas F Dluzen, Joshua E Muscat, Arthur Berg, Carla J Gallagher and Philip Lazarus

Cancer research (Chicago, Ill.), Vol.70(19), pp.7543-7552

10/01/2010

DOI: https://doi.org/10.1158/0008-5472.CAN-09-4582

Handle:

https://hdl.handle.net/2376/110845

PMID: 20876810

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Abstract

Mouth Mucosa - cytology

Minor Histocompatibility Antigens

Humans

Middle Aged

Genotype

Glucuronides - urine

Male

Smoking - genetics

Polymorphism, Genetic

Glucuronosyltransferase - genetics

Glucuronosyltransferase - metabolism

Mouth Mucosa - enzymology

Adult

Female

Aged

Smoking - urine

Nicotine - urine

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.

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Title: Glucuronidation genotypes and nicotine metabolic phenotypes: importance of functional UGT2B10 and UGT2B17 polymorphisms
Creators: Gang Chen - Molecular Epidemiology and Cancer Control Program, Penn State Cancer Institute, Department of Public Health Sciences, Penn State University College of Medicine, Hershey, Pennsylvania 17033, USA
Nino E Giambrone, Jr
Douglas F Dluzen
Joshua E Muscat
Arthur Berg
Carla J Gallagher
Philip Lazarus
Publication Details: Cancer research (Chicago, Ill.), Vol.70(19), pp.7543-7552
Academic Unit: Pharmaceutical Sciences, Department of
Publisher: United States
Grant note: R00 CA131477 / NCI NIH HHS R01 DE013158 / NIDCR NIH HHS P01 CA068384 / NCI NIH HHS R01-DE13158 / NIDCR NIH HHS P01-CA68384 / NCI NIH HHS
Identifiers: 99900546916501842
Language: English
Resource Type: Journal article