The most abundant and potent carcinogenic tobacco-specific nitrosamines in tobacco and tobacco smoke is 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). In vivo, NNK is rapidly metabolized to both the (R)- and (S)- enantiomers of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), which possesses similar carcinogenic properties as NNK. The major detoxification pathway for both NNAL enantiomers is glucuronidation by UDP-glucuronosyltransferase (UGT) enzymes including UGT2B10 and UGT2B17.
NNAL-N-Gluc, (R)-NNAL-O-Gluc, (S)-NNAL-O-Gluc and free NNAL were simultaneously and directly quantified in the urine of smokers by LC-MS analysis. Genotypes were determined by Taqman-assay using genomic DNA.
The average percentage of total urinary NNAL that existed as NNAL-N-Gluc, (R)-NNAL-O-Gluc, (S)-NNAL-O-Gluc, and free-NNAL in 180 active smokers was 23.2%, 21.7%, 26.9% and 28.2%, respectively. The functional knock-out polymorphism in the UGT2B10 gene at codon 67 (Asp>Tyr) was significantly (P<0.0001) associated with a 93% decrease in creatinine-adjusted NNAL-N-Gluc. The polymorphic whole-gene deletion of the UGT2B17 gene was associated with significant (P=0.0048) decreases in the levels of creatinine-adjusted (R)-NNAL-O-Gluc, with a 32% decrease in the levels of urinary (R)-NNAL-O-Gluc/(S)-NNAL-O-Gluc among subjects with the UGT2B17 (*2/*2) genotype as compared to subjects with the UGT2B17 (*1/*1) genotype.
These results suggest that functional polymorphisms in UGT2B10 and UGT2B17 are associated with a reduced detoxification capacity against NNAL and may therefore affect individual cancer risk upon exposure to tobacco.
This is the first report to clearly demonstrate strong genotype-phenotype associations between both the UGT2B10 codon 67 Asp<Tyr genotype and urinary NNAL-N-Gluc levels and between the UGT2B17 copy number variant and urinary (R)-NNAL-O-Gluc levels in smokers.
Pharmacology, Toxicology and Pharmaceutical Science
6
21%
Environmental Science
2
7%
Biochemistry, Genetics and Molecular Biology
2
7%
Agricultural and Biological Sciences
2
7%
Chemistry
2
7%
Other
2
7%
Unknown
13
45%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 3. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 28 September 2021.
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