Novel enzymological profiles of human 11beta-hydroxysteroid dehydrogenase type 1.
The human enzyme 11beta-hydroxysteroid dehydrogenase (11beta-HSD) catalyzes the reversible oxidoreduction of 11beta-OH/11-oxo groups of glucocorticoid hormones. Besides this important endocrinological property, the type 1 isozyme (11beta-HSD1) mediates reductive phase I reactions of several carbonyl group bearing xenobiotics, including drugs, insecticides and carcinogens. The aim of this study was to explore novel substrate specificities of human 11beta-HSD1, using heterologously expressed protein in the yeast system Pichia pastoris. In addition to established phase I xenobiotic substrates, 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. Purified recombinant 11beta-HSD1 mediated oxidative reactions, however, the labile reductive activity component could not be maintained. In conclusion, evidence is provided that human 11beta-HSD1 in vitro is involved in phase I reactions of anti-inflammatory non-steroidal drugs like ketoprofen and DFU-lactol.
Hult
M
M
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S 171 77, Stockholm, Sweden.
Nobel
C S
CS
Abrahmsen
L
L
Nicoll-Griffith
D A
DA
Jörnvall
H
H
Oppermann
U C
UC
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D066298:In Vitro Techniques; D007660:Ketoprofen / Q000378:metabolism; D010084:Oxidation-Reduction; D010843:Pichia / Q000235:genetics; D011355:Prodrugs / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity; D015262:Xenobiotics / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D011355:Prodrugs; D011994:Recombinant Proteins; D015262:Xenobiotics; D007660:Ketoprofen; D006913:Hydroxysteroid Dehydrogenases; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; C468387:HSD11B2 protein, human