Aromatic ring hydroxylation of estradiol in man.
Aromatic ring hydroxylation of estradiol in man.
复制标题
人体内雌二醇的芳环羟基化。
DOI：
10.1021/bi00809a018
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发表时间：
1970
期刊：
影响因子：
2.9
通讯作者：
L. Hellman
中科院分区：
文献类型：
--
作者：
J. Fishman;H. Guzik;L. Hellman
通过C-2代谢而被置换的氚出现在体内水中，其速率和程度与给予雌二醇17后的情况进行比较。酶和酸水解后获得的尿代谢物的同位素含量显示，2-含氧化合物占剂量的22%。这些代谢物是通过完全置换氚进行生物合成的。体内水分中的氚占剂量的33%，超过了排泄代谢物中的氚。有人建议，在给人类施用标记雌二醇后，体内多余的水分虽然变化很大，但大部分放射性并未出现在尿液中（Zumoff 等人，1968）。由于粪便中雌激素的排泄量很少（Beer 和 Gallagher，1955；Sandberg 和 Slaunwhite，1957），因此缺失物质的命运对调查来说是一个挑战。该实验室之前的一项研究（Fishman 等人，1966）采用了在 16a 和 16/3 处用氚进行立体特异性标记的雌二醇。结果表明，缺失的代谢物在 16a 时被取代，但在 16/3 时未被取代，因为排出的 16a-氧化代谢物加上未回收的剂量部分几乎精确地解释了从 estradiol-16a-3H 中释放的氚。目前的工作旨在找出导致缺失化合物的途径中涉及的 C-2 代谢程度。这是这种转化的合理位点，因为芳环 A 的裂解可能是雌二醇代谢物降解和损失的一种可能形式。制备了专门用atC-2氚标记的雌二醇并给予人体。在体液和尿液代谢物中监测氢同位素的命运，并将其与用碳 14 标记的分子的其余部分区分开来。该过程也有望揭示雌激素儿茶酚体内酶促形成的其他方面。
Tritium displaced by metabolism at C-2 appeared in the body water and its rate and extent was compared with that following estradiol-17-administration. The isotope con-tent of urinary metabolites obtained after enzyme and acid hydrolysis showed that 2-oxygenated compounds represented 22% of the dose. These metabolites were biosynthesized with complete displacement of tritium. The tritium in the body water was 33% of the dose and exceeded that derived from excreted metabolites. It is suggested that the excess body water ollowing the administration of labeled estradiol to man a varying but substantial portion of the radioactivity fails to appear in the urine (Zumoff et al., 1968). Since fecal excretion of estrogens is small (Beer and Gallagher, 1955; Sandberg and Slaunwhite, 1957) thefate of the missing material is a challenge for investigation. A previous study from this laboratory (Fishman et al., 1966) employed estradiols stereospecifically labeled with tritium at 16a and 16/3. It was demonstrated that the missing metabolites were substituted at 16a but not 16/3 since the excreted 16a-oxygenatedmetabolites plus the fraction of the dose that was not recovered almost precisely accounted for the tritium liberated from estradiol-16a-3H. The present work was initiated to find out the extent of metabolism at C-2 involved in the pathway leading to the missing compounds. This is a logical site for such transforma-tion since cleavage of the aromaticring A could be a likely form of degradation and loss of estradiol metabolites. Estradiol labeled specifically with tritium atC-2 was prepared and administered to man. The fate of the hydrogen isotope was monitored in body fluids as well as in the urinary metabolites and distinguished from the remainder of the molecule which was labeled with carbon-14. This procedure was also expected to shed light on other aspects of the enzymic in vivo formation of estrogen catechols.