Interindividuelle Unterschiede in der Aktivität und Expression der Nitrosaminketon reduzierenden Enzyme 11beta-Hydroxysteroid-Dehydrogenase Typ 1 und Carbonylreduktase in der menschlichen Lunge

The tobacco specific nitrosamine 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK), which is found in tobacco products and tobaco smoke, plays obviously an important role in the lung cancer induction in smokers. NNK requires metabolic activation by cytochrome P450 mediated alpha-hydroxylation to exhibit its carcinogenic properties by elektrophile metabolites and DNA alkylation. On the other hand, NNK is inactivated by carbonyl reduction to its alcohol-equivalent 4-methylnitrosamino-1-(3-pyridyl)-1-butanol (NNAL) followed by glucuronidation and final excretion into urine or bile. Microsomal 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD 1) (EC 1.1.1.146) and cytosolic carbonyl reductase (CR) (EC 1.1.1.184) have been shown to be mainly responsible for NNAL formation in liver and lung. They are subject of this study to show possible differences in the individual susceptibility of tobacco-smoke related lung cancer. Comparative investigations of human lung tissue samples from 17 patients were performed with respect to the expression and activity of 11beta-HSD 1 and carbonyl reductase. Varying levels in 11beta-HSD 1 and carbonyl reductase expression could be found in these patients, as revealed by RT-PCR (mRNA amounts) and ELISA (11beta-HSD 1 protein amounts in microsomes). Furthermore, the tissue samples showed a different activity and inhibitor profile for both enzymes (measured by chromatography of NNAL after tissue incubation with NNK). The different parameters for the patients are lacking correlations among each other. The variations in the expression and activity of NNK carbonyl reducing enzymes may constitute a determinant in the interindividually different NNK detoxification capacity and thus may be linked to the differences observed in the individual susceptibility of tobacco-smoke related lung cancer. Endogenous and exogenous factors, enzyme polymorphisms and for example so far unkown NNK reducing enzymes can play a role.