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

J. Halpert, J. Y. Jaw, L. J. Cornfield, C. Balfour, Eugene A Mash

Research output: Contribution to journalArticle

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Abstract

The inactivation by 21-chlorinated steroids of rat liver cytochromes P-450 involved in the hydroxylation of progesterone and androstenedione has been investigated. Preincubation of intact liver microsomes from phenobarbital-treated rats with 21-chloropregnenolone, 21,21-dichloropregnenolone, or 21,21-dichloroprogesterone in the presence of NADPH caused a time-dependent decrease in progesterone 21-hydroxylase and in progesterone or androstenedione 6β-hydroxylase activity but had negligible or only minor effects on five other steroid hydroxylases. The compounds differed, however, with regard to the relative rate constants for inactivation of the 21- and 6β-hydroxylases. For example, 21,21-dichloroprogesterone and 21,21-dichloropregnenolone inactivated the progesterone 6β-hydroxylase at similar rates, but the dichloroprogesterone was a more effective inactivator of the 21-hydroxylase. The results indicate that the introduction of a dichloromethyl group into a substrate bearing a methyl group normally hydroxylated by only one or a few isozymes of cytochrome P-450 may be a rational means of designing isozyme-selective inhibitors but that target and nontarget enzymes may not totally retain the regioselectivity they exhibit towards the underivatized substrate.

Original languageEnglish (US)
Pages (from-to)26-31
Number of pages6
JournalDrug Metabolism and Disposition
Volume17
Issue number1
StatePublished - 1989

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Chlorinated Steroids
Steroid 21-Hydroxylase
Androstenedione
Mixed Function Oxygenases
Liver
Cytochrome P-450 Enzyme System
Isoenzymes
Progesterone
Rats
Bearings (structural)
Steroid Hydroxylases
Regioselectivity
Hydroxylation
Substrates
Phenobarbital
NADP
Rate constants
Liver Microsomes
Enzymes
21,21-dichloroprogesterone

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

Selective inactivation of rat liver cytochromes P-450 by 21-chlorinated steroids. / Halpert, J.; Jaw, J. Y.; Cornfield, L. J.; Balfour, C.; Mash, Eugene A.

In: Drug Metabolism and Disposition, Vol. 17, No. 1, 1989, p. 26-31.

Research output: Contribution to journalArticle

Halpert, J, Jaw, JY, Cornfield, LJ, Balfour, C & Mash, EA 1989, 'Selective inactivation of rat liver cytochromes P-450 by 21-chlorinated steroids', Drug Metabolism and Disposition, vol. 17, no. 1, pp. 26-31.
Halpert, J. ; Jaw, J. Y. ; Cornfield, L. J. ; Balfour, C. ; Mash, Eugene A. / Selective inactivation of rat liver cytochromes P-450 by 21-chlorinated steroids. In: Drug Metabolism and Disposition. 1989 ; Vol. 17, No. 1. pp. 26-31.
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