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Specific inactivation by 17 beta-substituted steroids of rabbit and rat liver cytochromes P-450 responsible for progesterone 21-hydroxylation

J Halpert, JY Jaw and C Balfour

Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson 85721.

The selective inactivation by 17 beta-substituted steroids of rabbit and rat liver cytochromes P-450 involved in the 21-hydroxylation of progesterone has been investigated. Five derivatives each of pregnenolone and progesterone were prepared, in which the methylketo substituent of the 17 beta-position was replaced by a dichloromethylketo, chlorofluoromethylketo, difluoromethylketo, vinyl, or ethynyl group. The ability of the compounds to cause time-dependent (inactivation) and time-independent (inhibition) decreases in progesterone hydroxylase activity was assessed in vitro using intact liver microsomes as well as reconstituted systems containing the major forms of hepatic cytochrome P-450 responsible for progesterone 21- hydroxylation, P-450 1 in the rabbit and PB-C in the rat. In each species, one compound was identified that specifically inactivated the 21-hydroxylase, namely 21-chloro-21-fluoropregnenolone in the rabbit and pregn-4,20-diene-3-one in the rat, although both compounds inhibited several other hydroxylases as well. Moreover, the most effective and specific 21-hydroxylase inactivators were not necessarily the most effective or specific inhibitors. These results suggest that conversion of the enzyme-inhibitor complex to metabolites that inactivate the enzyme, rather than complex formation, is the crucial factor in determining the specificity of the compounds as cytochrome P- 450 inactivators. The results indicate the feasibility of designing specific inactivators of hepatic cytochromes P-450 by utilizing the normal regioselectivity of the target enzyme towards steroids.

Volume 35, Issue 1, pp. 148-156, 01/01/1989
Copyright © 1989 by American Society for Pharmacology and Experimental Therapeutics




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A. L. Blobaum
MECHANISM-BASED INACTIVATION AND REVERSIBILITY: IS THERE A NEW TREND IN THE INACTIVATION OF CYTOCHROME P450 ENZYMES?
Drug Metab. Dispos., January 1, 2006; 34(1): 1 - 7.
[Abstract] [Full Text] [PDF]


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