Bi H, Massé R
Institut National de la Recherche Scientifique, INRS-Santé, Université du Québec, Canada.
J Steroid Biochem Mol Biol. 1992 Jun;42(5):533-46. doi: 10.1016/0960-0760(92)90267-m.
The epimerization and dehydration reactions of the 17 beta-hydroxy group of anabolic 17 beta-hydroxy-17 alpha-methyl steroids have been investigated using the pyridinium salts of 17 beta-sulfate derivatives of methandienone 1, methyltestosterone 4, oxandrolone 7, mestanolone 10 and stanozolol 11 as model compounds. Rearrangement of the sulfate conjugates in buffered urine (pH 5.2) afforded the corresponding 17-epimers and 18-nor-17,17-dimethyl-13(14)-enes in a ratio of 0.8:1. These data indicated that both epimerization and dehydration of the 17 beta-sulfate derivatives were not dependent upon the respective chemical features of the steroids studied, but were instead inherent to the chemistry of the tertiary 17 beta-hydroxy group of these steroids. Interestingly, in vivo studies carried out with human male volunteers showed that only methandienone 1, methyltestosterone 4 and oxandrolone 7 yielded the corresponding 17-epimers 2, 5 and 8 and the 18-nor-17,17-dimethyl-13(14)-enes 3, 6 and 9 in ratios of 0.5:1, 2:1 and 2.7:1, respectively. No trace of the corresponding 17-epimers and 18-nor-17,17-dimethyl-13(14)-enes derivatives of mestanolone 10 and stanozolol 11 was detected in urine samples collected after administration of these steroids. These data suggested that the in vivo formation of the 17-epimers and 18-nor-17,17-dimethyl-13(14)-enes derivatives of 17 beta-hydroxy-17 alpha-methyl steroids is also dependent upon phase I and phase II metabolic reactions other than sulfation of the tertiary 17 beta-hydroxyl group, which are probably modulated by the respective chemical features of the steroidal substrates. The data reported in this study demonstrate that the 17-epimers and 18-nor-17,17-dimethyl-13(14)-enes are not artifacts resulting from the acidic or microbial degradation of the parent steroids in the gut as previously suggested by other authors, but arise from the rearrangement of their 17 beta-sulfate derivatives. Unchanged oxandrolone 7 was solely detected in the unconjugated steroid fraction whereas unchanged steroids 1, 4 and 11 were recovered from the glucuronide fraction. These data are indirect evidences suggesting that the glucuronide conjugates of compounds 1 and 4 are probably enol glucuronides and that of compound 11 is excreted in urine as a N-glucuronide involving its pyrazole moiety. The urinary excretion profiles of the epimeric and 18-nor-17,17-dimethyl-13(14)-ene steroids are presented and discussed on the basis of their structural features.
以美雄酮1、甲基睾酮4、氧雄龙7、美睾酮10和司坦唑醇11的17β-硫酸酯衍生物的吡啶盐作为模型化合物，研究了合成代谢的17β-羟基-17α-甲基甾体17β-羟基的差向异构化和脱水反应。硫酸酯共轭物在缓冲尿液（pH 5.2）中的重排产生了相应的17-差向异构体和18-降-17,17-二甲基-13(14)-烯，比例为0.8:1。这些数据表明，17β-硫酸酯衍生物的差向异构化和脱水反应并不取决于所研究甾体的各自化学特征，而是这些甾体叔17β-羟基化学性质所固有的。有趣的是，对人类男性志愿者进行的体内研究表明，只有美雄酮1、甲基睾酮4和氧雄龙7分别以0.5:1、2:1和2.7:1的比例产生相应的17-差向异构体2、5和8以及18-降-17,17-二甲基-13(14)-烯3、6和9。在给予这些甾体后收集的尿液样本中未检测到美睾酮10和司坦唑醇11相应的17-差向异构体和18-降-17,17-二甲基-13(14)-烯衍生物的痕迹。这些数据表明，17β-羟基-17α-甲基甾体的17-差向异构体和18-降-17,17-二甲基-13(14)-烯衍生物的体内形成也取决于I相和II相代谢反应，而不仅仅是叔17β-羟基的硫酸化反应，这可能受甾体底物各自化学特征的调节。本研究报告的数据表明，17-差向异构体和18-降-17,17-二甲基-13(14)-烯不是如其他作者先前所提出的那样是母体甾体在肠道中酸性或微生物降解产生的假象，而是由其17β-硫酸酯衍生物的重排产生的。未变化的氧雄龙7仅在未结合的甾体部分中检测到，而未变化的甾体1、4和11则从葡萄糖醛酸苷部分中回收。这些数据是间接证据，表明化合物1和4的葡萄糖醛酸苷共轭物可能是烯醇葡萄糖醛酸苷，而化合物11的葡萄糖醛酸苷以涉及其吡唑部分的N-葡萄糖醛酸苷形式排泄到尿液中。基于其结构特征，展示并讨论了差向异构和18-降-17,17-二甲基-13(14)-烯甾体的尿排泄谱。
