Expression and NNK reducing activities of carbonyl reductase and 11 beta-hydroxysteroid dehydrogenase type 1 in human lung

The tobacco specific nitrosamine 4-methylnitrosamino-1-(3-pyridyl)-1-butano ne (NNK), which is found in high amounts in tobacco products, is believed t o play an important role in lung cancer induction in smokers. NNK requires metabolic activation by cytochrome P450 mediated alpha -hydroxylation to ex hibit its carcinogenic properties. On the other hand, NNK is inactivated by carbonyl reduction to its alcohol-equivalent 4-methylnitrosamino-1-(3-pyri dyl)-1-butanol (NNAL) followed by glucuronidation and final excretion into urine or bile. Carbonyl reduction and alpha -hydroxylation are the predomin ant pathways in man, and it has been postulated that the extent of these co mpeting pathways determines the individual susceptibility to lung cancer. M oreover, only a minor part of all habitual smokers develop lung cancer, sug gesting the existence of susceptibility genes. Microsomal 11 beta -hydroxys teroid dehydrogenase type 1 (11 beta -HSD I) (EC 1.1.1.146) and cytosolic c arbonyl reductase (CR) (EC 1.1.1.184) have been shown to be mainly responsi ble for NNAL formation in liver and lung. In the present study, we performe d comparative investigations of human lung tissue samples from several pati ents with respect to the expression and activity of 11 beta -HSD 1 and carb onyl reductase. We observed varying levels in 11 beta -HSD 1 and carbonyl r eductase expression in these patients, as revealed by RT-PCR and ELISA. Als o, the tissue samples showed a different activity and inhibitor profile for both enzymes. According to our results, variations in the expression and a ctivity of NNK carbonyl reducing enzymes may constitute a major determinant in the overall NNK detoxification capacity and thus may be linked to the g reat differences observed in the individual susceptibility of tobacco-smoke related lung cancer. (C) 2001 Elsevier Science Ireland Ltd. All rights res erved.