The enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD; EC 1.1.1.146) is a microsomal enzyme-responsible for the interconversion of active 11β-hydroxycorticosteroids into inactive 11-ketocorticosteroids. Two distinct isozymes of 11β-HSD have been characterized so far. 11β-HSD 1 is mainly found in glucocorticoid target tissues where it may regulate steroid exposure to the glucocorticoid Type 11 receptor. 11β-HSD 2 has been considered to confer mineralocorticoid specificity on the nonselective Type 1 adrenocorticoid receptor by converting active 11-hydroxy glucocorticoids to receptor-inactive 11-oxo metabolites, in mineralocorticoid target tissues like the kidney. However, because of the much higher activities compared to that in kidney, liver 11β-HSD 1 possibly has additional functions besides the metabolism of glucocorticoids. We have isolated 11β-HSD 1 from liver microsomes and demonstrated that the homogenously purified enzyme is also capable of catalyzing the reductive metabolism of xenobiotic carbonyl compounds such as metyrapone, p-nitroacetophenone, p-nitrobenzaldehyde, menadione, and the tobacco-specific nitrosamine NNK. Inhibition experiments revealed strong sensitivity of xenobiotic carbonyl reduction to glucocorticoids and other endogenous steroids. The competitive nature of this inhibition suggests that both, steroids (glucocorticoids) and xenobiotic carbonyl substances bind to the same catalytically active site of 11β-HSD 1. It is concluded that 11β-HSD 1 plays an important role in phase-I biotransformation of pharmacologically relevant carbonyl substances as well as protecting organisms against toxic aldehydes, ketones and quinones by converting them to less lipophilic and more soluble and conjugatable metabolites. Thus, 11β-HSD 1 contributes to an expanding list of pluripotent hydroxysteroid dehydrogenases which are involved in reductive xenobiotic carbonyl metabolism as well as being specific towards their physiological steroid substrate.