White I N, Boobis A R, Davies D S
Biochem Pharmacol. 1984 Feb 1;33(3):459-64. doi: 10.1016/0006-2952(84)90241-7.
Metabolic activation of the ethynyl substituent of the contraceptive steroid norethindrone to cause the loss of hepatic cytochrome P-450 and the formation of green pigments has been compared in vivo and in vitro in rat, hamster, guinea pig, rabbit, mouse and hen and with marmoset and human liver microsomal preparations in vitro. In vivo green pigment accumulation in the liver 4 hr after the administration of norethindrone (100 mg/kg, i.p.) varied 60-fold between species. Male rat was the most active in this respect, the hen was the least active. The accumulation of green pigments in female rats was 27% that of male animals. This sex-dependent difference was not seen in male and female mice. Cytochrome P-450 destruction in vivo was also greatest in the male rat given norethindrone, whereas no loss was detected in the hen. In other species, however, the correlation between green pigment accumulation and cytochrome P-450 destruction was not particularly good. When liver microsomes were incubated with norethindrone and an NADPH generating system in vitro, the ranking order between species with respect to the initial rates of green pigment formation was similar to that based on the hepatic accumulation of these compounds found in vivo. Human liver microsomes showed initial rates of green pigment formation which were only 2% of that seen in the male rat. No destruction of human microsomal cytochrome P-450 caused by norethindrone could be detected. The HPLC elution profile of the green pigments produced in the liver following the administration of norethindrone differed between species. Hepatic microsomal preparations in contrast, at least with short incubation times, formed only one green pigment. Results suggest that further metabolism of either norethindrone or the green pigment, involving a cytosolic factor(s), results in the varied HPLC patterns seen in vivo.
在大鼠、仓鼠、豚鼠、兔子、小鼠和母鸡体内以及体外，并且在体外用人和狨猴的肝微粒体制剂，比较了避孕药类固醇炔诺酮的乙炔基取代基的代谢活化作用，该作用会导致肝细胞色素P - 450的丧失以及绿色色素的形成。给予炔诺酮（100mg/kg，腹腔注射）4小时后，肝脏中绿色色素的体内蓄积在不同物种间相差60倍。雄性大鼠在这方面最为活跃，母鸡最不活跃。雌性大鼠中绿色色素的蓄积量是雄性动物的27%。在雄性和雌性小鼠中未观察到这种性别依赖性差异。给予炔诺酮的雄性大鼠体内细胞色素P - 450的破坏也最大，而在母鸡中未检测到损失。然而，在其他物种中，绿色色素蓄积与细胞色素P - 450破坏之间的相关性并非特别好。当肝微粒体在体外与炔诺酮和一个NADPH生成系统一起孵育时，不同物种间绿色色素形成初始速率的排序与基于体内这些化合物在肝脏中的蓄积情况的排序相似。人肝微粒体显示的绿色色素形成初始速率仅为雄性大鼠的2%。未检测到炔诺酮对人微粒体细胞色素P - 450的破坏。给予炔诺酮后肝脏中产生的绿色色素的高效液相色谱洗脱图谱在不同物种间有所不同。相比之下，肝微粒体制剂，至少在短孵育时间下，仅形成一种绿色色素。结果表明，炔诺酮或绿色色素的进一步代谢，涉及一种或多种胞质因子，导致了在体内观察到的不同高效液相色谱模式。
