Structural modifications in contraceptive steroids altering their metabolism and toxicity

Area of Science:

• Pharmacology and Toxicology
• Biochemistry
• Drug Metabolism

Background:

• Norethisterone and d-norgestrel are synthetic progestagens.
• Metabolic activation of drugs can lead to toxic intermediates.
• Understanding drug metabolism is crucial for assessing safety.

Purpose of the Study:

• To investigate the metabolic activation and protein binding of norethisterone and d-norgestrel.
• To compare the binding potential of these progestagens with other steroids.
• To elucidate the mechanism and specificity of metabolite binding.

Main Methods:

• In vitro incubation with rat liver microsomes and NADPH.
• Measurement of irreversible protein binding of drug metabolites.
• Analysis of metabolite reactivity with various proteins (albumin, concanavalin A, gamma-globulin) and nucleic acids (DNA, RNA).

Main Results:

• Norethisterone and, to a lesser extent, d-norgestrel are activated to protein-binding intermediates by rat liver microsomes.
• Activation is NADPH-dependent and glutathione-inhibited.
• Norethisterone metabolites, particularly norethisterone-epoxide, show significant binding to albumin (SH-groups), while other proteins and nucleic acids do not react.
• Norgestrel metabolites exhibit lower reactivity compared to norethisterone.

Conclusions:

• The 19-nortestosterone progestagens norethisterone and norgestrel undergo metabolic activation to reactive epoxides.
• These epoxides preferentially bind to proteins containing sulfhydryl (SH) groups, similar to estrogens.
• The binding is specific and does not involve DNA or RNA, suggesting a mechanism distinct from genotoxicity.