Properties of Aldosterone Synthase and the Regulation Mechanism in Adrenocortex.

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Although a number of studies to date indicate that secretion of albosterone (ALD) is controlled by verious factors,such as ACTH,renin-angiotensin system,Na^+ and K^+,the interrelationship among these factors and the regulatory mechanism remain unresolved. This is mostly because of ambiguity of the enzyme which catalyzed the final step of ALD formation. Recent works have shown that purified cytochrome P-45011 has the activity of ALD formation from deoxycorticosterone (DOC) or corticosterone (COR), although very weak, besides intrinsic activities of 11 - and 18-hybroxylation of steroids. Such an observation,however,does not satisfy with many other observations so far obtained like ALD secretion limited in z-glomerulosa (z.G) and the presence of patients with inherited defect in ALD formation without deficiency in 11 -hydroxylase activity so on. We therefore incestigated the activities of individual reactions during the conversion of DOC to ALD in mitochondrial fractions of adrenocortical … More z.G and z.fasciculata (z.FR) of cow or rat under normal or abnormal physiological conditions,and then intended to isolate and characterize ALD synthase from bovine and rat adrenocortical mitochondria. Results we obtained were as follows:1) The intact mitochondria from z.G could produce more ALD than those from z.FR, showing distinct zonal specificity of ALD biosynthesis. When the mitochondria from both zones were sonicated, the activity became similar with each other, indicating the zonal specificity diminished and the integrity of the z.G mitochondria was essential to normal ALD production.2) Mitochondria from z.G of Na-depleted and K-repleted rats converted DOC or COR to 18-OH COR and ALD at several-to ten-fold higher retes than those of K-depleted and Na-repleted rats. However,the same preparations exhibited almost no difference in the 11 -and 18-hydroxylation of DOC.3) New P-450 species,49K protein,appeared in mitochondria only from z.G of rats with stimulated ALD biosynthesis.4) We purified 49K protein with a potent ALD synthesis activity from z.G of Na-depleted rats using HPLC hydroxylapatite column. This was completely separated from 51K protein (genuine cytochrome p-45011 ) and was designated as ALD synthase. The induction of 49K protein by various ftimuli of ALD biosynthesisare now in progress in our labolatory. Less