Studies on the Metabolism of Pregnenolone Sulfate1

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Abstract
The metabolism of pregnenolone-H3 sul-fate-S35 was studied both in vitro and in vivo. When the doubly labeled precursor was incubated with a hompgenate of neoplastic human adrenal tissue, 17[alpha]-hydroxypregnenolone-H were isolated as products. Conversion to doubly labeled dehydroisoandrosterone sulfate did not take place. A homogenate of human hyperplastic adrenal tissue, previously reported to convert pregnenolone-H3 sulfate-S35 to 17[alpha]-hydroxypreg-nenolone-H3 sulfate-S35 in the absence of significant conversion to dehydroisoandrosterone -H3 sulfate-S35 (18), was, in the presently reported studies, shown to possess the ability to transform pregnenolone to A4-androstenedione. When pregnenolone-H3 sulfate-S35 was injected into a female patient with an adrenal carcinoma, extensive metabolism to a variety of urinary metabolites was observed. Five crystalline substances were isolated and identified pregnenediol 3-sulfate, 17[alpha]-hy-droxypregnenolone 3-sulfate, pregnenetriol 3-sulfate, dehydroisoandrosterone sulfate and androstenediol 3-sulfate. The first 2 crystalline substances were isolated from a biological source for the first time. Pregnenediol 3-sulfate, dehydroisoandrosterone sulfate and androstenediol 3-sulfate were recrystallized to radiochemical homogeneity with respect to H3 and S35. The presence of pregnenetriol-H3 3-sulfate-S35 was demonstrated by oxidation withperiodate to a doubly labeled product whose chromatographic mobility was identical with that of dehydroisoandrosterone sulfate. However, the identity of the isotope associated with 17[alpha]-hydroxypregnenolone 3-sulfate was not established. Pregnenediol 3-sulfate possessed a H3 to S35 ratio higher than that injected, whereas the isotope ratio in dehydroisoandrosterone sulfate, androstenediol 3-sulfate and pregnenetriol 3-sulfate was significantly lower than that administered. Since the specific activity of pregnenediol 3-sulfate with respect to S35 was more than 100 times as great as those of dehydroisoandrosterone sulfate, androstenediol 3-sulfate and pregnenetriol 3-sulfate, it is concluded that essentially all of the S35-labeled pregnenediol 3-sulfate and therefore a major portion of the tritiated pregnenediol 3-sulfate arose by a metabolic pathway involving intact steroid sulfates as intermediates. It is not clear, on the other hand, whether any portion of the S35-label in dehydroisoandrosterone sulfate, androstenediol 3-sulfate or pregnenetriol 3-sulfate was derived from pregnenolone sulfate by transformation of intact S35 labeled steroid sulfates, although it is certain that these conjugates, labeled with tritium, were in vivo metabolites of pregnenolone-H3 sulfate.