Abstract
Norethisterone, specifically labeled with tritium, was incubated with hepatic microsomes of rats. About 2% of 3H radioactivity was irreversibly incorporated into the microsomal protein. This protein binding of norethisterone (about 0.7-1.6 nmol/mg of microsomal protein) was dependent on oxygen, NADPH, substrate concentration, and microsomal protein content and could be inhibited by carbon monoxide. Glutathione and other cysteine derivatives with free sulfhydryl groups diminished the microsomal protein binding as did the addition of bovine serum albumin. Norethisterone-derived radioactivity was also irreversibly bound to albumin. Solvent-extraction and charcoal-adsorption methods were employed to prove the irreversible nature of this binding. After trypsin digestion of albumin and microsomal protein loaded with norethisterone, peptides which were labeled with 3H could be isolated. To explain our results, a metabolic bioactivation of norethisterone to norethisterone-4,5-epoxide, catalyzed by the microsomal mixed-function oxidase cytochrome P-450, is proposed.
Footnotes
- Received May 5, 1975.
- Copyright © 1975 by The American Society for Pharmacology and Experimental Therapeutics
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