The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-l -butanone (NNK), which is generated by nitrosation of nicotine, requires enzymatic activation by cytochrome-P450-mediated n-carbon hydroxylation to yield particularly powerful carcinogenic alkylating intermediates. Pyridine-N-oxidation and carbonyl reduction are detoxification pathways, the latter by providing the functional hydroxy moiety necessary for glucuronosylation and final excretion of NNK. For more than a decade, the enzyme responsible for NNK carbonyl reduction has awaited characterization. In the present study, we demonstrate that the NNK carbonyl reductase is identical to 1 I/?-hydroxysteroid dehydrogenase (1 lP-HSD), the physiological function of which is the oxidoreduction of glucocorticoids. We conclude that the expression of 1 1P-HSD (together with glucuronosyl transferase) may have profound influence on the carcinogenic potency of NNK and that many compounds of endogenous and exogenous origin, which are known to be substrates or inhibitors of 11P-HSD, may modulate NNK-induced carcinogenicity by competing for the same enzyme. In light of the known species and tissue differences in the expression of 11P-HSD isozymes, important aspects of NNK-induced tumorigenesis, such as metabolic activation versus inactivation or organospecificity, can now be re-evaluated.

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Myosmine has been regarded as a specific tobacco alkaloid until investigations pointed out that nuts and nut products constitute a significant source of myosmine. In the present study it is shown that the occurrence of myosmine is widespread throughout a large number of plant families. Using a method for extraction practicable for all examined foods, quantitative analysis through internal standard addition showed nanograms per gram amounts. Positively tested edibles were staple foods such as maize, rice, wheat flour, millet, potato, and milk and also cocoa, popcorn, tomato, carrot, pineapple, kiwi, and apples. No myosmine was detectable in other vegetables and fruits such as lettuce, spinach, cucumber, onion, banana, tangerines, and grapes. Myosmine is easily nitrosated giving rise to a DNA adduct identical to the esophageal tobacco carcinogen N-nitrosonornicotine. Therefore, the role of dietary myosmine in esophageal adenocarcinoma should be further investigated.

1 The most frequently used biomarkers for exposure to environmental tobacco smoke (ETS) are cotinine and thiocyanate in body fluids, carboxyhaemoglobin in red blood cells (COHb) and carbon monoxide in the expired air. Although not ideal, cotinine in blood, saliva or urine is an established biomarker for ETS exposure within the past 1-3 days. Comparison with cotinine concentrations in cigarette smokers reveals that passive smokers take up less than 1/100 of the nicotine dose of smokers. 2 Biomonitoring data available for the ETS-related exposure to genotoxic substances comprise uptake of benzene, polycyclic aromatic hydrocarbons (PAH), aromatic amines, tobacco-specific nitrosamines (TSNA), electrophilic compounds giving rise to ur inary thioethers, mutagens causing urinary mutagenic activity and the formation of various DNA adducts. With the exception of TSNA, these biomarkers are related to chemicals occurring ubiquitously in the environment and in the food. As a consequence, the background levels in unexposed nonsmokers are high compared to the observed increases (if any) associated with ETS exposure. 3 Some markers of biological effects, which, by defini tion, are non-specific with regard to the underlying exposure, have also been investigated in relation to ETS exposure. These markers comprise cytogenetic effects, aryl hydrocarbon hydroxylase (AHH) induc tion, urinary hydroxyproline excretion and various factors indicative of cardiovascular risks. The avail able data suggest that passive smoking is associated with a small induction of placental AHH and also with effects on cardiovascular risk markers. The latter findings in particular may be confounded by other risk factors, which have been observed to be more frequent in passive smokers than in unexposed nonsmokers.

Recent studies suggest a direct contribution of nicotine, the addictive component of tobacco and tobacco smoke, to human carcinogenesis. To assess the genotoxicity of nicotine, the DNA-damaging effect on human lymphocytes and target cells from lymphatic tissue of the palatine tonsils from 10 healthy patients was tested with the alkaline single-cell microgel electrophoresis (Comet) assay. The degree of DNA migration, a measure of possible DNA single strand breaks, alkali labile sites, and incomplete excision repair sites, was expressed as the Olive tail moment, the percentage of DNA in the tail, and the tail length. One hour exposure to nicotine at 0.125, 0.25, 0.5, 1, 2, and 4 mM induced a statistically significant dose-dependent increase of DNA migration up to 3.8-fold and 3.2-fold in tonsillar cells and lymphocytes, respectively. The lowest concentration eliciting significant DNA damage was 0.5 mM nicotine. The genotoxic effect was confirmed in a second series of experiments using nicotine of high purity from two different suppliers. There were no significant differences between the two series, excluding artifacts from the source of nicotine. Finally, DNA damage by nicotine was compared in cells incubated in medium strictly adjusted to neutral pH, with non-adjusted medium becoming alkaline with increasing nicotine concentrations. Again no differences in DNA migration were observed. The data indicate that nicotine expresses significant direct genotoxic effects in human target cells in vitro. However, no differences in DNA damage were observed in cells from smokers and nonsmokers incubated without nicotine. The lack of higher DNA damage in smokers compared to nonsmokers could be a question of nicotine dose, rapid DNA repair, or interactions with other smoke constituents. These results require further investigations on the contribution of nicotine to tobacco carcinogenesis.