Novel enzymological profiles of human 11 beta-hydroxysteroid dehydrogenasetype 1

The human enzyme 11 beta -hydroxysteroid dehydrogenase (11 beta -HSD) catal yzes the reversible oxidoreduction of 11 beta -OH/11-oxo groups of glucocor ticoid hormones. Besides this important endocrinological property, the type 1 isozyme (11 beta -HSD1) mediates reductive phase I reactions of several carbonyl group bearing xenobiotics, including drugs, insecticides and carci nogens. The aim of this study was to explore novel substrate specificities of human 11 beta -HSD1, using heterologously expressed protein in the yeast system Pichia pastoris. In addition to established phase I xenobiotic subs trates, it is now demonstrated that transformed yeast strains catalyze the reduction of ketoprofen to its hydroxy metabolite, and the oxidation of the prodrug DFU-lactol to the pharmacologically active lactone compound. Purif ied recombinant 11 beta -HSD1 mediated oxidative reactions, however, the la bile reductive activity component could not be maintained. In conclusion, e vidence is provided that human 11 beta -HSD1 in vitro is involved in phase I reactions of anti-inflammatory non-steroidal drugs like ketoprofen and DF U-lactol. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.