Bolt H M
Arch Toxicol. 1977 Dec 30;39(1-2):13-9. doi: 10.1007/BF00343271.
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.
炔诺酮以及在较小程度上的d - 炔诺孕酮可被大鼠肝脏微粒体酶代谢活化为能够与蛋白质不可逆结合的中间体。这种体外微粒体活化依赖于NADPH的存在，并受到谷胱甘肽的抑制。与炔诺酮代谢物相比，孕酮、醋酸诺睾酮和醋酸环丙孕酮的代谢物的不可逆结合非常低。苯酚作为参考化合物在定量上显示出与炔诺酮相似的结合行为。炔诺酮 - 4β,5β - 环氧化物是炔诺酮的一种微粒体代谢物，以每小时380 pmol/mg白蛋白的速率（在37摄氏度下）非酶促地与白蛋白结合。炔诺孕酮 - 4β,5β - 环氧化物的相应速率为每小时42 pmol/mg白蛋白，表明炔诺孕酮环氧化物的反应性明显较低。非SH - 蛋白伴刀豆球蛋白A和牛γ - 球蛋白与炔诺酮环氧化物或炔诺孕酮环氧化物均无反应。此外，DNA和RNA也没有结合反应。因此，19 - 去甲睾酮类孕激素炔诺酮和炔诺孕酮不可逆结合蛋白的要求与雌激素相似，雌激素经大鼠肝脏微粒体活化后，仅与具有SH基团的蛋白质结合，而不与DNA或RNA结合。
