Cytochrome P450 2A-Catalyzed Metabolic Activation of Structurally Similar Carcinogenic Nitrosamines:  N‘-Nitrosonornicotine Enantiomers, N-Nitrosopiperidine, and N-Nitrosopyrrolidine

Wong, Hansen; Murphy, Sharon E.; Hecht, Stephen S.

doi:10.1021/tx0497696

Cited by 96 publications

(95 citation statements)

References 54 publications

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“…Mouse P450 2A5 is an excellent catalyst of 5′-hydroxylation of both (R)-and (S)-NNN, and several other P450 2A enzymes including rat 2A3, mouse 2A4, human 2A6, and human 2A13 are also reasonably efficient (30). Lower activity of P450 2A enzymes was found for 2′-hydroxylation of (R)-NNN, and none was found for 2′-hydroxylation of (S)-NNN.…”

Section: Tobacco-specific Nitrosamines: Metabolism Dna Adduct Formatmentioning

confidence: 98%

Progress and Challenges in Selected Areas of Tobacco Carcinogenesis

Hecht

2007

Chem. Res. Toxicol.

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Tobacco use continues to be a major cause of cancer in the developed world, and despite significant progress in this country in tobacco control, which is driving a decrease in cancer mortality, there are still over 1 billion smokers in the world. This perspective discusses some selected issues in tobacco carcinogenesis focusing on progress during the 20 years of publication of Chemical Research in Toxicology. The topics covered include metabolism and DNA modification by tobacco-specific nitrosamines, tobacco carcinogen biomarkers, an unidentified DNA ethylating agent in cigarette smoke, mutations in the K-RAS and p53 gene in tobacco-induced lung cancer and their possible relationship to specific carcinogens, secondhand smoke and lung cancer, emerging issues in smokeless tobacco use, and a conceptual model for understanding tobacco carcinogenesis. It is hoped that a better understanding of mechanisms of tobaccoinduced cancer will lead to new and useful approaches for the prevention of lung cancer and other cancers caused by tobacco use.

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Section: Tobacco-specific Nitrosamines: Metabolism Dna Adduct Formatmentioning

confidence: 98%

Progress and Challenges in Selected Areas of Tobacco Carcinogenesis

Hecht

2007

Chem. Res. Toxicol.

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260

242

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“…CYP2A5 is active toward numerous drugs and other xenobiotic compounds (Su and Ding, 2004;Wong et al, 2005;Raunio et al, 2008), including many nasal toxicants, such as the herbicide dichlobenil and the antithyroid drug methimazole . Previous studies using recombinant P450 enzymes have shown that human CYP2A6 and CYP2A13, orthologs of mouse CYP2A5, are both active in NA bioactivation (Cho et al, 2006;Fukami et al, 2008); however, evidence for a role of CYP2A5 in mediating the toxicity of NA has yet to be obtained.…”

Section: Introductionmentioning

confidence: 99%

Essential Role of the Cytochrome P450 Enzyme CYP2A5 in Olfactory Mucosal Toxicity of Naphthalene

et al. 2013

Drug Metab Dispos

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Naphthalene (NA), a ubiquitous environmental pollutant that can cause pulmonary and nasal toxicity in laboratory animals, requires cytochrome P450 (P450)-mediated metabolic activation to cause toxicity. Our recent study using a Cyp2f2-null mouse showed that CYP2F2 plays an essential role in NA-induced lung toxicity, but not in NA-induced nasal toxicity. The aim of this study was to determine whether mouse CYP2A5, abundantly expressed in nasal olfactory mucosa (OM) and the liver, but less in the lung, plays a major role in the bioactivation and toxicity of NA in the OM. We found, by comparing Cyp2a5-null and wild-type (WT) mice, that the loss of CYP2A5 expression led to substantial decreases in rates of NA metabolic activation by OM microsomes. The loss of CYP2A5 did not cause changes in systemic clearance of NA (at 200 mg/kg, i.p.). However, the Cyp2a5-null mice were much more resistant than were WT mice to NA-induced nasal toxicity (although not lung toxicity), when examined at 24 hours after NA dosing (at 200 mg/kg, i.p.), or to NA-induced depletion of total nonprotein sulfhydryl in the OM (although not in the lung), examined at 2 hours after dosing. Thus, mouse CYP2A5 plays an essential role in the bioactivation and toxicity of NA in the OM, but not in the lung. Our findings further illustrate the tissue-specific nature of the role of individual P450 enzymes in xenobiotic toxicity, and provide the basis for a more reliable assessment of the potential risks of NA nasal toxicity in humans.

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“…In humans, CYP2A6 and CYP2A13 are important catalysts of NNN and NNK ␣-hydroxylation (Jalas et al, 2005;Wong et al, 2005a). The high efficiency of CYP2A13 for NNK metabolic activation combined with its expression in respiratory tissues, including nasal mucosa, lung, and trachea, suggests that CYP2A13 plays a critical role in tobacco-specific nitrosamine-induced carcinogenesis (Su et al, 2000;Jalas et al, 2005;Wong et al, 2005b;Zhu et al, 2006).…”

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confidence: 99%

Effect of CYP2A13 Active Site Mutation N297A on Metabolism of Coumarin and Tobacco-Specific Nitrosamines

2008

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ABSTRACT:Cytochrome P450 2A13-catalyzed ␣-hydroxylation is a critical step in the activation of the tobacco carcinogens 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and (S)-N-nitrosonornicotine [(S)-NNN]. In the enzyme's active site, a single polar residue, Asn297, can influence substrate binding, orientation, and metabolism. We determined the effects of N297A mutation on enzyme kinetics and specificity for NNK, NNN, and coumarin metabolism. (Hecht, 1998). Both NNN and NNK require P450-catalyzed metabolism to exert their carcinogenic effects (Hecht, 1998). Metabolic activation occurs by hydroxylation of the carbons ␣ to the nitroso moiety. For NNN, hydroxylation occurs at the 2Ј-and 5Ј-carbon positions to ultimately form 4-oxo-4-(3-pyridyl)-1-butanol (keto alcohol), 5-(3-pyridyl)-2-hydroxytetrahydrofuran (lactol), and reactive diazohydroxide intermediates (Fig. 1). Hydroxylation of NNK occurs at the ␣-methyl and ␣-methylene carbon positions, forming keto alcohol, 4-oxo-4-(3-pyridyl)-1-butanone (keto aldehyde), and two diazohydroxides that are capable of pyridyloxobutylating or methylating DNA (Fig. 1).CYP2A13 is the most efficient human P450 catalyst of NNK ␣-hydroxylation (Jalas et al., 2005). It is a 300-fold more efficient catalyst than the hepatic enzyme CYP2A6, despite 93.5% sequence identity between these enzymes. The X-ray crystal structures for CYP2A6 and CYP2A13 have been reported previously (Yano et al., 2005;Smith et al., 2007). The active sites of CYP2A6 and CYP2A13 share several similar characteristics. These include a cluster of phenylalanine residues that line the "roof" of the active site and the presence of a single polar residue, Asn297. Docking NNK into the crystal structures of CYP2A13 and CYP2A6 predicts, because of a slightly different active site volume and shape, that the orientation of NNK in CYP2A13 is more favorable for ␣-hydroxylation . In both enzymes, a hydrogen bond between NNK and Asn297 seems to affect substrate orientation. With CYP2A6, the hydrogen bond forms between Asn297 and the carbonyl oxygen of NNK, and with CYP2A13 it is between Asn297 and the pyridine nitrogen; only the latter orientation is compatible with ␣-hydroxylation.

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Cytochrome P450 2A-Catalyzed Metabolic Activation of Structurally Similar Carcinogenic Nitrosamines: N‘-Nitrosonornicotine Enantiomers, N-Nitrosopiperidine, and N-Nitrosopyrrolidine

Cited by 96 publications

References 54 publications

Progress and Challenges in Selected Areas of Tobacco Carcinogenesis

Progress and Challenges in Selected Areas of Tobacco Carcinogenesis

Essential Role of the Cytochrome P450 Enzyme CYP2A5 in Olfactory Mucosal Toxicity of Naphthalene

Effect of CYP2A13 Active Site Mutation N297A on Metabolism of Coumarin and Tobacco-Specific Nitrosamines

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