PT  - JOURNAL ARTICLE
AU  - J Halpert
AU  - J Y Jaw
AU  - C Balfour
TI  - Specific inactivation by 17 beta-substituted steroids of rabbit and rat liver cytochromes P-450 responsible for progesterone 21-hydroxylation.
DP  - 1989 Jan 01
TA  - Molecular Pharmacology
PG  - 148--156
VI  - 35
IP  - 1
4099  - http://molpharm.aspetjournals.org/content/35/1/148.short
4100  - http://molpharm.aspetjournals.org/content/35/1/148.full
SO  - Mol Pharmacol1989 Jan 01; 35
AB  - 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.