Effect of Nicotine and Cotinine on NNK Metabolism in Rats

Kutzer, C.; Richter, Elmar; Oehlmann, C.; Atawodi, Sunday E.

doi:10.1007/978-3-0348-7445-8_50

Cited by 6 publications

(7 citation statements)

References 7 publications

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“…The third part of NNK metabolites in the urine of rats is mainly composed of N-oxides of NNK and NNAL. Only very small amounts of NNAL and NNALGlu are excreted into the urine of rats (Kutzer et al 1995). In humans NNAL-Glu as well as free NNAL have been detected in the urine of smokers, snuff dippers and nonsmokers experimentally exposed to high concentrations of sidestream cigarette smoke Murphy et al 1994).…”

Section: Discussionmentioning

confidence: 99%

Metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in isolated rat lung and liver

Schrader

Hirsch‐Ernst

Richter

et al. 1998

Naunyn-Schmiedeberg's Arch Pharmacol

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The tobacco specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a strong lung carcinogen in all species tested. To elicit its tumorigenic effects NNK requires metabolic activation which is supposed to take place via alpha-hydroxylation, whereas N-oxidation is suggested to be a detoxification pathway. The differences in the organ specific metabolism of NNK may be crucial for the organotropy in NNK-induced carcinogenesis. Therefore, metabolism of NNK was investigated in the target organ lung and in liver of Fischer 344 (F344) rats using the model of isolated perfused organs. High activity to metabolize 35 nM [5-3H]NNK was observed in both perfused organs. NNK was eliminated by liver substantially faster (clearance 6.9 +/- 1.6 ml/min, half-life 14.6 +/- 1.2 min) than by lung (clearance 2.1 +/- 0.5 ml/min, half-life 47.9 +/- 7.4 min). When the clearance is calculated for a gram of organ or for metabolically active cell forms, the risk with respect to carcinogenic mechanisms was higher in lung than in liver. The metabolism of NNK in liver yielded the two products of NNK alpha-hydroxylation, the 4-oxo-4-(3-pyridyl)-butyric acid (keto acid) and 4-hydroxy-4-(3-pyridyl)-butyric acid (hydroxy acid). In lung, the major metabolite of NNK was 4-(methylnitrosamino)-1-(3-pyridyl-N-oxide)-1-butanone (NNK-N-oxide). Substantial amounts of metabolites formed from methyl hydroxylation of NNK, which is one of the two possible pathways of alpha-hydroxylation, were detected in lung but not in liver perfusion. Formation of these metabolites (4-oxo-4-(3-pyridyl)-butanol (keto alcohol), and 4-hydroxy-4-(3-pyridyl)-butanol (diol) can give rise to pyridyloxobutylating of DNA. When isolated rat livers were perfused with 150 microM NNK, equal to a dosage which is sufficient to induce liver tumors in rat, glucuronidation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) was increased when compared to the concentration of 35 nM NNK. Nevertheless, the main part of NNK was also transformed via alpha-hydroxylation for this high concentration of NNK.

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Section: Discussionmentioning

confidence: 99%

Metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in isolated rat lung and liver

Schrader

Hirsch‐Ernst

Richter

et al. 1998

Naunyn-Schmiedeberg's Arch Pharmacol

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“…Therefore, experiments were performed to investigate wether nicotine and its main metabolite cotinine affect NNK metabolism in intact organs. In several studies nicotine has been shown to inhibit the metabolic activation of NNK in vivo (Richter and Tricker 1994;Kutzer et al 1995) and in vitro (Murphy and Heiblum 1990;Hong et al 1992).…”

Section: Discussionmentioning

confidence: 99%

Effect of nicotine or cotinine on metabolism of 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK) in isolated rat lung and liver

Schulze

Schrader

Foth

et al. 1998

Naunyn-Schmiedeberg's Arch Pharmacol

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The scope of the present study was to investigate whether nicotine or cotinine will affect the metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in isolated perfused rat lungs and livers and to study the effect of starvation on pulmonary metabolism of NNK. NNK metabolism was investigated in isolated perfused liver and lung of male F344 rats perfused with 35 nM [5-3H]NNK in presence of a 1400-fold excess of the main tobacco alkaloid nicotine and its metabolite cotinine. In perfused rat livers, nicotine and cotinine inhibited NNK elimination and metabolism and led to a substantial increase of elimination half-life from 14.6 min in controls to 25.5 min after nicotine and 36.6 min after cotinine co-administration, respectively. In parallel, the pattern of NNK metabolites was changed by nicotine and cotinine. The pathway of alpha-hydroxylation representing the metabolic activation of NNK was decreased to 77% and 85% of control values, whereas N-oxidation of NNK and glucuronidation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) was increased 2.6- and 1.2-fold in presence of nicotine and cotinine, respectively. When isolated rat lungs were perfused with 35 nM NNK for 3 h neither the elimination nor the pattern of metabolites were substantially affected due to co-administration of 50 microM nicotine or cotinine. Cytochrome P450 2E1 is known to participate in the activation of NNK and can be induced by starvation. However, isolated rat lungs from male Sprague Dawley rats perfused with [1-14C]NNK at about 2 microM for 3 h, revealed only small differences in pulmonary elimination and pattern of NNK metabolites between fed and starved animals. These results suggest that nicotine and its main metabolite cotinine inhibit the metabolic activation of NNK predominantly in the liver whereas activation in lung, a main target organ of NNK induced carcinogenesis, remained almost unaffected.

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“…It is therefore possible, that at more realistic exposures, and where the relation between the levels of protective agents and TSNA is more favorable, a still higher degree of protection can be attained. It is possible, though, that at least part of the inhibition can be ascribed to inhibition of α-hydroxylation by nicotine and cotinine mentioned above [42,45].…”

Section: Modulation Of the Carcinogenic Effects Of Tsnamentioning

confidence: 95%

“…The inhibition of the NNK α-hydroxylation pathway by nicotine, cotinine and NNN constitutes an important observation, where the suppression of metabolic activation involves a shift towards increase of detoxification. As a consequence there is an increased excretion of pyridine-N-oxides and NNAL-glucuronides as well as a reduction in the generation of HPB haemoglobin adducts [42,45]. There is also considerable species variation with respect to the metabolism of NNK and NNN.…”

Section: Metabolic Transformations Of Tsnamentioning

confidence: 97%

“…However, by the main route of conversion, α-hydroxymethyl-NNK leads to the formation of 4-(3-pyridyl)-4-oxobutane-1-diazohydroxide that introduces covalently bound pyridyloxobutyl adducts at nucleophilic centers in DNA and proteins. Mild acid or alkaline hydrolysis of these adducts releases 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB), which can be derivatized and conveniently analyzed by GC-MS [40][41][42]. Minor metabolic pathways involve the hydroxylation of the 6-position of the pyri dine ring of NNK, and pyridine-N-oxidation of NNK and NNAL.…”

Section: Metabolic Transformations Of Tsnamentioning

confidence: 99%

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De Minimus Non Curat Lex - Virtual Thresholds for Cancer Initiation by Tobacco Specific Nitrosamines - Prospects for Harm Reduction by Smokeless Tobacco

Nilsson

2006

International Journal of Occupational Medicine and Environmental Health

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Whereas the impact of tobacco specific nitrosamines in smokers is obscured by the presence of numerous other carcinogens and promoters, for smokeless tobacco virtually all the carcinogenic potential is associated with 4-(nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN). In some countries exposure to smokeless tobacco with extremely high nitrosamine concentrations have been found to induce cancers in the head-neck region, whereas three recent large epidemiological studies failed to detect any such risk with respect to Swedish low-nitrosamine snuff. This review deals with quantitative aspects of DNA adduct formation from NNN and NNK in relation to the background levels ubiquitously found in healthy humans without known exposures to either tobacco or alkylating agents. The lack of significant increases of pro-mutagenic O6-methylations and DNA pyridyloxobutylations seen in smokers, as well as the negative outcome of the Swedish epidemiological studies, can be expected on basis of extrapolation of the dose response relationships found in rodents to actual exposures to NNK and NNN in Swedish snuff or from smoking. Sweden has the lowest prevalence of male smokers and smoking related diseases in the Western World, which has been ascribed to the fact that more than 20% of the grown up male population uses snuff. Smokeless tobacco represents an inexpensive and effective alternative to nicotine delivering products like nicotine patch, spray or gum. Considering that all other tobacco products are freely marketed, the ban on low-nitrosamine snuff in all countries in EU except Sweden is difficult to defend on either medical or ethical grounds.

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Effect of Nicotine and Cotinine on NNK Metabolism in Rats

Cited by 6 publications

References 7 publications

Metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in isolated rat lung and liver

Metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in isolated rat lung and liver

Effect of nicotine or cotinine on metabolism of 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK) in isolated rat lung and liver

De Minimus Non Curat Lex - Virtual Thresholds for Cancer Initiation by Tobacco Specific Nitrosamines - Prospects for Harm Reduction by Smokeless Tobacco

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