Sex-specificity in lung cancer risk.

Smoking is indisputably linked to lung cancer, yet only a small fraction of smokers develops this disease. Although previously tobacco-derived carcinogens and enzyme polymorphisms have been identified to increase the risk for smokers, recent epidemiological data suggest even sex-specificity as a new and additional factor. Obviously, women have a higher risk to develop lung cancer upon smoking than men.

Expression and activity of the cortisol-activating enzyme 11β-hydroxysteroid dehydrogenase type 1 is tissue and species-specific.

The microsomal enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) interconverts glucocorticoid receptor-inert cortisone (11-dehydrocorticosterone in rodents) to its receptor-active form cortisol (corticosterone in rodents). Thus, 11β-HSD1 amplifies glucocorticoid action at the tissue level. According to the current literature, dysregulation of glucocorticoid signaling may contribute to the pathogenesis of the metabolic syndrome in which regeneration of cortisol by 11β-HSD1 may be an important factor.

Different inhibitory potential of sex hormones on NNK detoxification in vitro: A possible explanation for gender-specific lung cancer risk.

Smoking women are probably at a higher risk to develop lung cancer than men. Different explanations exist for these findings, a gender-specific impairment of tobacco carcinogen metabolism being one of them. In this study, we examined the inhibition of NNK reduction to NNAL, the first and most important detoxication step of this tobacco-specific carcinogen.

Sex hormones reduce NNK detoxification through inhibition of short-chain dehydrogenases/reductases and aldo-keto reductases in vitro.

Carbonyl reduction is an important metabolic pathway for endogenous and xenobiotic substances. The tobacco specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK, nicotine-derived nitrosamine ketone) is classified as carcinogenic to humans (IARC, Group 1) and considered to play the most important role in tobacco-related lung carcinogenesis. Detoxification of NNK through carbonyl reduction is catalyzed by members of the AKR- and the SDR-superfamilies which include AKR1B10, AKR1C1, AKR1C2, AKR1C4, 11β-HSD1 and CBR1.

Green tea and one of its constituents, Epigallocatechine-3-gallate, are potent inhibitors of human 11β-hydroxysteroid dehydrogenase type 1.

The microsomal enzyme 11β-hydroxysteroid deydrogenase type 1 (11β-HSD1) catalyzes the interconversion of glucocorticoid receptor-inert cortisone to receptor- active cortisol, thereby acting as an intracellular switch for regulating the access of glucocorticoid hormones to the glucocorticoid receptor. There is strong evidence for an important aetiological role of 11β-HSD1 in various metabolic disorders including insulin resistance, diabetes type 2, hypertension, dyslipidemia and obesity. Hence, modulation of 11β-HSD1 activity with selective inhibitors is being pursued as a new therapeutic approach for the treatment of the metabolic syndrome.