Interindividual variability in the expression and NNK carbonyl reductase activity of 11 beta-hydroxysteroid dehydrogenase 1 in human lung

The balance between metabolic activation and detoxification is critical in determining the susceptibility to lung cancer upon exposure to the tobacco specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Carbonyl reduction of NNK, followed by glucuronidation, is the main detoxi fication pathway of this lung carcinogen in humans. Recently, we have ident ified 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD 1) as micros omal NNK carbonyl reductase in liver and lung. In the present study, the in terindividual variability of 11 beta-HSD 1 expression and NNK-carbonyl redu ctase activity was examined in human lung by RT-PCR, Western blot analysis and enzyme activity. Levels of 11 beta-HSD 1 mRNA varied over an almost 20- fold range among different subjects. Levels of NNK carbonyl reductase activ ity in lung microsomes closely resembled the relative amounts of immunoreac tive protein as determined by Western blot analysis. In view of the large i nterindividual differences in the susceptibility of tobacco smoke related l ung cancer, we present the first data on the variability of 11 beta-HSD 1 e xpression and NNK carbonyl reduction in human lung. (C) 1999 Elsevier Scien ce Ireland Ltd. All rights reserved.