Structural modifications in contraceptive steroids altering their metabolism and toxicity.

Norethisterone and, to a lesser extent, d-norgestrel are metabolically activated by rat liver microsomal enzymes to intermediates which are capable of irreversibly binding to proteins. This microsomal activation in vitro depends on presence of NADPH and is inhibited by glutathione. Irreversible binding of metabolites of progesterone, nortestosterone acetate and cyproterone acetate is very low, compared to that of norethisterone metabolites. Phenol as a reference compound shows quantitatively a similar binding behaviour as norethisterone. Norethisterone-4beta,5beta-epoxide, a microsomal metabolite of norethisterone, binds non-enzymatically to albumin, at a rate of 380 pmol/mg albumin per hour (at 37 degrees). The corresponding rate for norgestrel-4beta,5beta-epoxide, 42 pmol/mg albumin per hour, indicates a considerably lower reactivity of norgestrel-epoxide. The non-SH-proteins concanavalin A and bovine gamma-globulin do not react with either norethisterone-epoxide or norgestrel-epoxide. Also, DNA and RNA show no binding reaction. Thus, the requirements for irreversible protein binding of the 19-nortestosterone progestagens norethisterone and norgestrel are similar to those found for oestrogens which, when activated by rat liver microsomes, only bind to proteins with SH-groups, not to DNA or RNA.