Cytochrome P450 Enzymes as Catalysts of Metabolism of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone, a Tobacco Specific Carcinogen

Jalas, John R.; Hecht, Stephen S.; Murphy, Sharon E.

doi:10.1021/tx049847p

Cited by 142 publications

(178 citation statements)

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“…A review published in 1988 mentions the importance of characterizing which P450s are involved in NNK metabolism, but no data were available at that time (6). Presently, steady state kinetic parameters for P450-catalyzed NNK metabolism have been reported for eight human enzymes, two rabbit enzymes, five rat enzymes, and two mouse enzymes (20). Human P450s 2A13 and 2B6, rat P450 2A3, and mouse P450 2A5 may be the most important catalysts of NNK metabolic activation in these species, based on their kinetic parameters.…”

Section: Tobacco-specific Nitrosamines: Metabolism Dna Adduct Formatmentioning

confidence: 99%

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: 99%

Progress and Challenges in Selected Areas of Tobacco Carcinogenesis

Hecht

2007

Chem. Res. Toxicol.

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260

242

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“…P450 enzymes have been shown to play major roles in activating these carcinogens, based on the analysis of formation of chemically reactive metabolites, DNA adduct and damage, chromosomal abbreviation, and bacterial mutagenicity and genotoxicity assays such as Ames and umu test systems (2)(3)(4)(5)(6)(7)(8). Our previous studies using umu genotoxicity assay with human P450 enzymes in conjunction with the results obtained from Ames mutagenicity assay and other detection systems reported so far (6,(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) have suggested that human CYP1A1, 1A2, 1B1, 2A6, 2A13, 2E1, and 3A4 are major enzymes involved in the activation of various environmental carcinogens including PAHs and tobacco-related nitrosamines (Table 1).…”

Section: T Shimadamentioning

confidence: 99%

“…CYP2A6 and 2A13 are expressed mainly in the liver and respiratory tract, respectively, in humans (4,138,139). CYP2A6 is active in catalyzing metabolism of several drugs, e.g.…”

Section: Fig 2 Effects Of Preincubation Time On Inhibition Of Cyp1amentioning

confidence: 99%

Inhibition of Carcinogen-Activating Cytochrome P450 Enzymes by Xenobiotic Chemicals in Relation to Antimutagenicity and Anticarcinogenicity

Shimada

2017

ToxicolRes

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A variety of xenobiotic chemicals, such as polycyclic aromatic hydrocarbons (PAHs), aryl-and heterocyclic amines and tobacco related nitrosamines, are ubiquitous environmental carcinogens and are required to be activated to chemically reactive metabolites by xenobiotic-metabolizing enzymes, including cytochrome P450 (P450 or CYP), in order to initiate cell transformation. Of various human P450 enzymes determined to date, CYP1A1, 1A2, 1B1, 2A13, 2A6, 2E1, and 3A4 are reported to play critical roles in the bioactivation of these carcinogenic chemicals. In vivo studies have shown that disruption of Cyp1b1 and Cyp2a5 genes in mice resulted in suppression of tumor formation caused by 7,12-dimethylbenz[a]anthracene and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, respectively. In addition, specific inhibitors for CYP1 and 2A enzymes are able to suppress tumor formation caused by several carcinogens in experimental animals in vivo, when these inhibitors are applied before or just after the administration of carcinogens. In this review, we describe recent progress, including our own studies done during past decade, on the nature of inhibitors of human CYP1 and CYP2A enzymes that have been shown to activate carcinogenic PAHs and tobacco-related nitrosamines, respectively, in humans. The inhibitors considered here include a variety of carcinogenic and/or non-carcinogenic PAHs and acethylenic PAHs, many flavonoid derivatives, derivatives of naphthalene, phenanthrene, biphenyl, and pyrene and chemopreventive organoselenium compounds, such as benzyl selenocyanate and benzyl selenocyanate; o-XSC, 1,2-, 1,3-, and 1,4-phenylenebis(methylene)selenocyanate.

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“…NNK requires metabolic activation for expression of its carcinogenicity (Jalas et al, 2005). The metabolic activation of NNK has been shown to result in the formation of reactive intermediates that can interact with cellular nucleophiles (Fig.…”

Section: Introductionmentioning

confidence: 99%

“…Carbonyl reduction of NNK, which is one of the major pathways, produces 4-(methylnitrosamino)-1 -(3-pyridyl)-1-butanol (NNAL) (Carmella et al, 1993). NNAL is also a potent carcinogen and requires metabolic activation to exert its carcinogenic effects (Hecht, 1998;Jalas et al, 2005). On the other hand, NNK and NNAL are inactivated through oxidation of their pyri-dine nitrogen (Castonguay et al, 1983).…”

Section: Introductionmentioning

confidence: 99%

Tissue distributions of 4-(hydroxymethylnitrosamino)-1-(3-pyridyl)-1-butanone glucuronide, a stable form of reactive intermediate produced from 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, in the rat

et al. 2014

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-The tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), induces lung tumors in rodents and has been suggested as a causative factor in human lung cancer. NNK is activated by α-hydroxylation at either the methyl or methylene carbon adjacent to the N-nitroso group to yield unstable intermediates that spontaneously decompose to produce alkylating agents. 4-(Hydroxymethylnitrosamino)-1-(3-pyridyl)-1-butanone (HO-methyl NNK) glucuronide, a glucuronide of the reactive intermediate of NNK has been identified. However, there are no available data concerning HO-methyl NNK glucuronide. In the present study, we investigated the tissue distribution of HO-methyl NNK glucuronide in control and phenobarbital (PB)-treated rats after intraperitoneal administration of NNK. In PB-treated rats, HO-methyl NNK glucuronide was detected in plasma, kidney, liver, lung, and pancreas. On the contrary, in the control rats, HO-methyl NNK glucuronide was detected only in plasma, kidney and liver at low concentrations compared with PB-treated rats. The results of cumulative urinary excretion of HO-methyl NNK glucuronide in Wistar and Gunn rats suggested that PB-inducible UDP-glucuronosyltransferase 2B isoforms mainly contribute to the formation of HO-methyl NNK glucuronide.

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Cytochrome P450 Enzymes as Catalysts of Metabolism of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone, a Tobacco Specific Carcinogen

Cited by 142 publications

References 74 publications

Progress and Challenges in Selected Areas of Tobacco Carcinogenesis

Progress and Challenges in Selected Areas of Tobacco Carcinogenesis

Inhibition of Carcinogen-Activating Cytochrome P450 Enzymes by Xenobiotic Chemicals in Relation to Antimutagenicity and Anticarcinogenicity

Tissue distributions of 4-(hydroxymethylnitrosamino)-1-(3-pyridyl)-1-butanone glucuronide, a stable form of reactive intermediate produced from 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, in the rat

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