Comparative Metabolism of the Tobacco-Specific Nitrosamines 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone and 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanol by Rat Cytochrome P450 2a3 and Human Cytochrome P450 2a13

Jalas, John R.; Ding, Xinxin; Murphy, Sharon E.

doi:10.1124/dmd.31.10.1199

Cited by 63 publications

(59 citation statements)

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“…Urinary NNAL levels from exposure to secondhand smoke is about 30 times lower than from exposure to active smoking (24), and there is little information that suggests that TTFC might be related to exposure to secondhand smoke in active smokers. The major metabolic activation pathways of NNK and its proximate metabolite NNAL occur by a-hydroxylation, whereas the detoxification of NNAL to NNAL-Gluc occurs by glucuronidation (25). While there may be interindividual differences in the metabolism of NNK and NNAL, NNAL is an excellent indicator of tobacco carcinogen exposure and particularly useful in epidemiologic studies because unlike many other known tobacco carcinogens, it is not found in other environmental sources.…”

Section: Discussionmentioning

confidence: 99%

Time to First Cigarette and 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanol (NNAL) Levels in Adult Smokers; National Health and Nutrition Examination Survey (NHANES), 2007–2010

Branstetter

Muscat

2013

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background: The time to first cigarette (TTFC) is a good indicator of several dimensions of nicotine dependence. An early TTFC is also associated with increased lung and oral cancer risk. Our objective was to determine the relationship between TTFC and exposure to tobacco smoke carcinogens.Methods: We conducted a cross-sectional analysis of a nationally representative subsample of smoking adults that had urinary samples analyzed for tobacco biomarkers. The study included 1,945 participants from the 2007-2008 and 2009-2010 National Health and Nutrition and Examination Survey. The main outcome measure was creatinine-adjusted urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) levels.Results: The cigarette-per-day adjusted levels of NNAL were twice as high in participants who smoked within 5 minutes after waking than in participants who refrained from smoking for at least 1 hour (0.58 vs. 0.28 ng/mL, P < 0.001). In multivariate linear models, a shorter TTFC was significantly associated with increasing NNAL levels, after adjusting for cigarettes smoked per day (or cotinine), secondhand smoke exposure, age, sex, race/ethnicity, and other potential confounders.Conclusions: These data show that in a nationally representative sample, there is a dose-dependent relationship between earlier smoking in the day and higher biologic exposure to a tobacco smoke carcinogen.Impact: Our study provides further evidence that highlights the relationship between TTFC, nicotine dependence, and cancer risk. Cancer Epidemiol Biomarkers Prev; 22(4); 615-22. Ó2013 AACR.

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Section: Discussionmentioning

confidence: 99%

Time to First Cigarette and 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanol (NNAL) Levels in Adult Smokers; National Health and Nutrition Examination Survey (NHANES), 2007–2010

Branstetter

Muscat

2013

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…The differences in NNK and NNAL metabolism may be due to differences in the affinity of different P450 isoforms for NNK versus NNAL as a result of differences in polarity between the keto group of NNK and the hydroxyl group of NNAL. In fact, Jalas et al (2003) found that CYP2A enzymes are more efficient catalysts of NNK metabolism than of NNAL metabolism.…”

Section: Discussionmentioning

confidence: 99%

Analysis of CYP2A Contributions to Metabolism of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone in Human Peripheral Lung Microsomes

Brown

Bedard²,

Reid³

et al. 2007

Drug Metab Dispos

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ABSTRACT:The objectives of this study were to determine the contributions of CYP2A13 and CYP2A6 to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) metabolism in human peripheral lung microsomes and to determine the influence of the genetic polymorphism, CYP2A13 Arg257Cys, on NNK metabolism. 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), the keto-reduced metabolite of NNK, was the major metabolite produced, ranging from 0.28 to 0.9%/mg protein/min. Based on total bioactivation of NNK and NNAL by ␣-carbon hydroxylation, subjects could be classified as either high (17 subjects) or low (12 subjects) bioactivators [(5.26 ؎ 1.23) ؋ 10 ؊2 and (6.49 ؎ 5.90) ؋ 10 ؊3% total ␣-hydroxylation/mg protein/min, P < 0.05]. Similarly, for detoxification, subjects could be grouped into high (9 subjects) and low (20 subjects) categories [(2.03 ؎ 1.65) ؋ 10 ؊3 and (2.50 ؎ 3.04) ؋ 10 ؊4% total N-oxidation/mg protein/min, P < 0.05]. When examining data from all individuals, no significant correlations were found between levels of CYP2A mRNA, CYP2A enzyme activity, or CYP2A immunoinhibition and the degree of total NNK bioactivation or detoxification (P > 0.05). However, subgroups of individuals were identified for whom CYP2A13 mRNA correlated with total NNK and NNAL ␣-hydroxylation and NNAL-N-oxide formation (P < 0.05). The degree of NNAL formation and CYP2A13 mRNA was also correlated (P < 0.05). Subjects (n ‫؍‬ 84) were genotyped for the CYP2A13 Arg257Cys polymorphism, and NNK metabolism for the one variant (Arg/Cys) was similar to that for other subjects. Although results do not support CYP2A13 or CYP2A6 as predominant contributors to NNK bioactivation and detoxification in peripheral lung of all individuals, CYP2A13 may be important in some.Lung cancer is the leading cause of cancer-related death in the world, and it is estimated that cigarette smoking accounts for approximately 90% of lung cancer cases (Hecht, 2003). The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is thought to play a major role in human tobacco-related cancers (Hecht, 2003). NNK is the most prevalent pulmonary carcinogen in tobacco smoke and the most potent cancer-causing tobacco-specific nitrosamine in all animal species tested (Hecht, 1998). NNK selectively induces lung adenocarcinoma in animals (Hecht, 1998) and is believed to be a causal agent in the induction of human lung adenocarcinoma, which is now the leading form of lung cancer (Hoffmann et al., 1996;Thun et al., 1997).To induce carcinogenesis, NNK and its keto-reduced metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), require metabolic activation via ␣-carbon hydroxylation (Fig. 1). Hydroxylation of the ␣-methylene carbons of NNK and NNAL leads to the formation of DNA-methylating species, whereas hydroxylation of the ␣-methyl carbons of NNK and NNAL results in the formation of DNA-pyridyloxobutylating and -pyridylhydroxybutylating species, respectively. The formation of both types of adducts is believed to be important in the induction of ...

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“…Although a solution initially containing a 1:1 ratio of CYP2A13 to cytochrome b 5 was used to grow the crystals, and density weakly suggestive of cytochrome b 5 was present in the channels of the P450 crystalline lattice, it was not strong enough to model cytochrome b 5 .…”

Section: Methodsmentioning

confidence: 99%

“…Structures of CYP2A13 with NNK Bound-NNK can be oxidized by CYP2A13 at either carbon ␣ to the nitrosamine. The dominant metabolite (5, 7, 9) results from hydroxylation of the ␣-methylene, but the ␣-methyl can also be hydroxylated with about a 3-fold lower K cat /K m (5,7,9). NNK bound to CYP2A13 in two different orientations in different molecules of the CYP2A13/NNK P1 structure and in yet another orientation in the CYP2A13/NNK I422 structure.…”

Section: Dissociation Constants For Nicotine and Nnk-nicotinementioning

confidence: 99%

Nicotine and 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone Binding and Access Channel in Human Cytochrome P450 2A6 and 2A13 Enzymes

DeVore

Scott

2012

Journal of Biological Chemistry

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Background: Cytochromes P450 2A13 and 2A6 are involved in nicotine metabolism and tobacco-related lung cancer initiation. Results: CYP2A13 and CYP2A6 structures were solved with nicotine and CYP2A13 with NNK. Conclusion: Structure series reveals basis for nicotine and NNK selectivity and access to buried active site. Significance: Understanding CYP2A binding and oxidation of pharmacological substrates can aid in drug development efforts.

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Comparative Metabolism of the Tobacco-Specific Nitrosamines 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone and 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanol by Rat Cytochrome P450 2a3 and Human Cytochrome P450 2a13

Cited by 63 publications

References 10 publications

Time to First Cigarette and 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanol (NNAL) Levels in Adult Smokers; National Health and Nutrition Examination Survey (NHANES), 2007–2010

Time to First Cigarette and 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanol (NNAL) Levels in Adult Smokers; National Health and Nutrition Examination Survey (NHANES), 2007–2010

Analysis of CYP2A Contributions to Metabolism of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone in Human Peripheral Lung Microsomes

Nicotine and 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone Binding and Access Channel in Human Cytochrome P450 2A6 and 2A13 Enzymes

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