The Identification of 11β‐hydroxysteroid Dehydrogenase as Carbonyl Reductase of the Tobacco‐Specific Nitrosamine 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanone

The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), which is generated by nitrosation of nicotine, requires enzymatic activation by cytochrome-P450-mediated α-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 11β-hydroxysteroid dehydrogenase (11β-HSD), the physiological function of which is the oxidoreduction of glucocorticoids. We conclude that the expression of 11 β-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 11β-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 11β-HSD isozymes, important aspects of NNK-induced tumorigenesis, such as metabolic activation versus inactivation or organospecificity, can now be re-evaluated.