The novel anticancer drug oracin: different stereospecificity and cooperativity for carbonyl reduction by purified human liver 11beta-hydroxysteroid dehydrogenase type 1.
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| Abstract |
Inherent or acquired resistance of tumor cells to anti-cancer drugs is a problem of major importance in chemotherapy. In addition to detailed research into the mechanisms of drug inactivation, attention has also been paid to the synthesis of new structures. Oracin is a promising cytostatic drug, which is presently in phase II of clinical trials. This investigation was designed to characterize the metabolic inactivation of oracin by carbonyl reduction to 11-dihydrooracin (DHO). We identified 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD 1) as the principal enzyme being responsible for oracin carbonyl reduction in human liver microsomes. The purified 11beta-HSD 1 catalyses this reaction in a stereospecific manner. Formation of (-)-DHO surpasses that of (+)-DHO by a factor of around four. Moreover, 11beta-HSD 1 exhibits enzyme cooperativity for the formation of both enantiomers (Hill coefficients of 2.26 +/- 0.20 and 1.84 +/- 0.29 for (-)-DHO and (+)-DHO, respectively). Comparing the differences in the stereospecificity and Hill coefficients between the microsomes and purified 11beta-HSD 1 could anticipate contribution of another microsomal enzyme. In case of oracin, this enzyme cooperativity may become important with respect to maximal plasma concentrations, and, by inhibition of 11beta-HSD 1, to enhance the chemotherapeutic efficacy of this anti-cancer drug.
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| Authors | Vladimír Wsól, Barbora Szotáková, Lenka Skálová, Edmund Maser |
| Journal | Toxicology (Toxicology) Vol. 197 Issue 3 Pg. 253-61 (May 03 2004) ISSN: 0300-483X [Print] Ireland |
| PMID | 15033547 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
| Chemical References |
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