Study on the mechanism of biosynthesis of 19-nor-stenroids and its application for analysis of pathgeneeis

11-脱氧皮质酮（DOC）在离体牛肾上腺皮质中存在另一条代谢途径：DOC-19-OH-DOC-19-oxo-DOC-19-oic-DOC.对DOC的11<beta>-、18-和19-羟基化活性的比较研究表明，DOC的19-羟基化，以及11 -和18-羟基化，都有相当高的羟基化速率<beta>.另外，19-OH-DOC和19-oxo-DOC在19-位的氧化反应速率比DOC的19-羟基化反应速率高约5倍。这些结果表明，尽管19-OH-DOC和19-oxo-DOC对DOC的亲和力较低，但DOC的C-19氧化途径是存在的，而且这些氧化反应需要还原型吡啶核苷酸（NADPH）和分子氧。此外，一氧化碳或甲吡酮（0.01-1.0 M）的存在均匀地抑制了这三种氧化反应<micrn>，已知甲吡酮与细胞色素P-450特异性结合，而氰化钾（0.01- 0.1 mM）对它们没有影响。这些结果表明，在DOC、19-OH-DOC和19-Oic-DOC的C-19氧化反应中，细胞色素P-450的参与是可能的。我们还表明，19-oic-DOC是DOC在肾上腺中代谢的最终产物，并且它可以进一步在肾上腺外转化为19-nor-DOC。

We have demonstrated the presence of an alternative metabolic pathway of 11-deoxycorticosterone(DOC) in bovine adrenal cortex in vitro: DOC---19-OH-DOC---19-oxo-DOC---19-oic-DOC.Comparative studies of 11<beta>-, 18-, and 19-hydroxylation activities of reveled that an appreciable level of hydroxylation rate was observed in 19-hydroxylation of DOC, as well as in 11<beta>-, and 18-hydroxylations. In addition,the rates of the oxidation reactions of 19-OH-DOC and 19-oxo-DOC at the 19-position were about 5 times higher than those of the 19-hydroxylation of DOC. These resultus suggest the presence of the pathway of the C-19 oxidation of DOC, although the affinities of 19-OH-DOC and 19oxo-DOC for the enzyme(s) were lower than that of DOC.It was also established that reduced pyridine nucleotibe(NADPH) and molecular oxygen were required for these oxidation reactions. In addition, these three oxidation reactions were uniformly inhibited by the presence of carbon monoxide or metyrapone(0.01-1.0<micrn>M), which is known to bind Specifically with cytochrome P-450, while potassium cyanide(0.01-0.1mM) did not affect them. These results suggest the possibility of the inbolbe-ment of cytochrome P-450 in the C-19 oxidation reactions of DOC,19-OH-DOC and 19-oic-DOC. We have also shown that 19-oic-DOC is the final product of the metabolism of DOC in the adrenal gland and that it may further be converted to 19-nor-DOC extraadrenally.