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Selective inactivation of rat liver cytochromes P-450 by 21-chlorinated steroids

J Halpert1, J Y Jaw, L J Cornfield

  • 1Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson 85721.

Drug Metabolism and Disposition: the Biological Fate of Chemicals
|January 1, 1989
PubMed

Insights

21-Chlorinated steroids selectively inactivate specific rat liver cytochrome P-450 enzymes involved in steroid hydroxylation. This research offers insights into designing targeted inhibitors for cytochrome P-450 isozymes.

Area of Science:

  • Biochemistry
  • Enzymology
  • Pharmacology

Background:

  • Cytochromes P-450 (CYP450) are crucial enzymes in steroid metabolism.
  • Specific CYP450 isozymes catalyze progesterone and androstenedione hydroxylation.
  • Understanding CYP450 inhibition is vital for drug development and metabolic studies.

Purpose of the Study:

  • To investigate the inactivation of rat liver CYP450 isozymes by 21-chlorinated steroids.
  • To determine the selectivity of these chlorinated steroids against specific steroid hydroxylase activities.
  • To evaluate the potential of these compounds as isozyme-selective inhibitors.

Main Methods:

  • Incubation of rat liver microsomes with 21-chloropregnenolone, 21,21-dichloropregnenolone, and 21,21-dichloroprogesterone.
  • Assay of progesterone 21-hydroxylase and 6 beta-hydroxylase activities.
  • Measurement of inactivation kinetics and comparison with other steroid hydroxylases.

Main Results:

  • 21-Chlorinated steroids caused time-dependent inactivation of progesterone 21-hydroxylase and 6 beta-hydroxylase.
  • Inactivation showed selectivity, with minor effects on five other steroid hydroxylases.
  • Different chlorinated steroids exhibited varying inactivation rates for 21- and 6 beta-hydroxylases, with 21,21-dichloroprogesterone being more effective for 21-hydroxylation.

Conclusions:

  • Introduction of a dichloromethyl group can yield isozyme-selective CYP450 inhibitors.
  • The regioselectivity of target and non-target enzymes may be altered by these inhibitors.
  • These findings contribute to the rational design of specific CYP450 modulators.

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