Metabolites of 4-(N-methylnitrosamino)- 1-(3-pyridyl)-1-butanone in urine of smokers

Meger, Michael; Meger-Kossien, Irmtrud; Dietrich, M; Tricker, Anthony R.; Scherer, Gerhard; Adlkofer, F.

doi:10.1097/00008469-199609001-00025

Cited by 6 publications

(6 citation statements)

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“…In contrast to the results in rodents, the patas monkey excretes substantial amounts of NNAL-Gluc in urine at low doses (160). This led to the development of methods to quantify NNAL-Gluc in human urine (162,166,170). Levels of NNAL-Gluc are generally greater than those of NNAL in human urine, and both exceed those of NNAL N-oxide (168).…”

Section: T H Imentioning

confidence: 99%

“…NNK and NNK N-oxide have not been detected in human urine (166,168). The ratio NNAL-Gluc:NNAL has been suggested as an index of detoxification of NNK in humans, and this ratio varies widely (162,166,170). Presently, we do not know if NNAL-Gluc is a detoxification product of NNAL, although metabolic studies indicate that only about 10% is ultimately converted to R-hydroxylation products in rats (152).…”

Section: T H Imentioning

confidence: 99%

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Biochemistry, Biology, and Carcinogenicity of Tobacco-Specific N-Nitrosamines

Hecht

1998

Chem. Res. Toxicol.

1,003

1,372

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Section: T H Imentioning

confidence: 99%

Section: T H Imentioning

confidence: 99%

Biochemistry, Biology, and Carcinogenicity of Tobacco-Specific N-Nitrosamines

Hecht

1998

Chem. Res. Toxicol.

1,003

1,372

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“…It is, therefore, important to study the tissue distribution of NNK-activating and NNK-inactivating enzymes in order to understand the biochemical mechanisms of NNK carcinogenesis. Several studies on the profile of NNK metabolites in smokers' urine have revealed high interindividual variations with respect to NNAL, NNAL-glucuronide, and NNAL-Noxide quantities (Carmella et al, 1995;Meger et al, 1996). It is these variations that are of greatest interest since they may not only be linked to lung cancer susceptibility, but also to a genetic polymorphism in terms of NNK reductase expression.…”

Section: Protection Against Tobacco Smoke-derived Lung Cancermentioning

confidence: 99%

Carbonyl Reductases and Pluripotent Hydroxysteroid Dehydrogenases of the Short-chain Dehydrogenase/reductase Superfamily

Hoffmann¹,

Maser²

2007

Drug Metabolism Reviews

199

124

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Carbonyl reduction of aldehydes, ketones, and quinones to their corresponding hydroxy derivatives plays an important role in the phase I metabolism of many endogenous (biogenic aldehydes, steroids, prostaglandins, reactive lipid peroxidation products) and xenobiotic (pharmacologic drugs, carcinogens, toxicants) compounds. Carbonyl-reducing enzymes are grouped into two large protein superfamilies: the aldo-keto reductases (AKR) and the short-chain dehydrogenases/reductases (SDR). Whereas aldehyde reductase and aldose reductase are AKRs, several forms of carbonyl reductase belong to the SDRs. In addition, there exist a variety of pluripotent hydroxysteroid dehydrogenases (HSDs) of both superfamilies that specifically catalyze the oxidoreduction at different positions of the steroid nucleus and also catalyze, rather nonspecifically, the reductive metabolism of a great number of nonsteroidal carbonyl compounds. The present review summarizes recent findings on carbonyl reductases and pluripotent HSDs of the SDR protein superfamily.

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“…Some scientists have hypothesized that ingested tobacco alkaloids, such as nicotine, might contribute to TSNA formation within the human body (Hoffmann et al 1994; Hecht and Hoffmann 1989). Others have published data that support the conclusion that endogenous TSNA formation does not occur (Fischer et al 1990; Caldwell et al 1991; Meger et al 1995; Adlkofer 1995; Spiegelhalder and Fischer 1990; Hecht et al 1999; Tricker et al 1993). The hypothesis of endogenous TSNA formation conflicts with recent evidence that smoking cessation therapies that involve the administration of nicotine in the form of gum, patch, and/or inhalers do not lead to endogenous TSNA formation (Hecht et al 1999).…”

Section: Nnk and Other Tsna In Tobacco And Tobacco Smokementioning

confidence: 92%

An Analysis of the Role of Tobacco-Specific Nitrosamines in the Carcinogenicity of Tobacco Smoke

Brown

Borschke

Doolittle

2003

Nonlinearity in Biology, Toxicology, Medicine

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Cigarette smoke is a complex mixture consisting of more than 4500 chemicals, including several tobacco-specific nitrosamines (TSNA). TSNA typically form in tobacco during the post-harvest period, with some fraction being transferred into mainstream smoke when a cigarette is burned during use. The most studied of the TSNA is 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). NNK has been shown to be carcinogenic in laboratory animals. Studies examining the carcinogenicity of NNK frequently are conducted by injecting rodents with a single dose of 2.5 to 10 mumol of pure NNK; the amount of NNK contained in all of the mainstream smoke from about 3700 to 14,800 typical U.S. cigarettes. Extrapolated to a 70-kg smoker, the carcinogenic dose of pure NNK administered to rodents would be equivalent to the amount of NNK in all of the mainstream smoke of 22 to 87 million typical U.S. cigarettes. Furthermore, extrapolating results from rodent studies based on a single injection of pure NNK to establish a causative role for NNK in the carcinogenicity of chronic tobacco smoke exposure in humans is not consistent with basic pharmacological and toxicological principles. For example, such an approach fails to consider the effect of other smoke constituents upon the toxicity of NNK. In vitro studies demonstrate that nicotine, cotinine, and aqueous cigarette "tar" extract (ACTE) all inhibit the mutagenic activity of NNK. In vivo studies reveal that the formation of pulmonary DNA adducts in mice injected with NNK is inhibited by the administration of cotinine and mainstream cigarette smoke. Cigarette smoke has been shown to modulate the metabolism of NNK, providing a mechanism for the inhibitory effects of cigarette smoke and cigarette smoke constituents on NNK-induced tumorigenesis. NNK-related pulmonary DNA adducts have not been detected in rodents exposed to cigarette smoke, nor has the toxicity of tobacco smoke or tobacco smoke condensate containing marked reductions in TSNA concentrations been shown to be reduced in any biological assay. In summary, there is no experimental evidence to suggest that reduction of TSNA will reduce the mutagenic, cytotoxic, or carcinogenic potential of tobacco smoke.

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Metabolites of 4-(N-methylnitrosamino)- 1-(3-pyridyl)-1-butanone in urine of smokers

Cited by 6 publications

References 0 publications

Biochemistry, Biology, and Carcinogenicity of Tobacco-Specific N-Nitrosamines

Biochemistry, Biology, and Carcinogenicity of Tobacco-Specific N-Nitrosamines

Carbonyl Reductases and Pluripotent Hydroxysteroid Dehydrogenases of the Short-chain Dehydrogenase/reductase Superfamily

An Analysis of the Role of Tobacco-Specific Nitrosamines in the Carcinogenicity of Tobacco Smoke

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