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Adrenocortical steroids are synthesized in the endoplasmic reticulum, and polyunsaturated fatty acids (PUFAs) inhibit the rate of steroid formation by the adrenal, kidney, and ovary, but not by the liver. Adrenocortical conversion of progesterone to 11-deoxycorticosterone was inhibited by 20:4n-6 at an initial rate of 0.23 nmol/10 min/mg mitochondrial protein and 20:5n-3 at 0.68 nmol/10 min/mg protein. Adrenocortical steroids formed by the adrenal cortex, kidney, and ovary were inhibited by 20:4n-6 at an initial rate of 0.79, 1.19, and 1.85 nmol/10 min/mg mitochondrial protein, respectively, and 20:5n-3 at 1.40 nmol/10 min/mg protein. Fatty acid inhibition was not related to decreased steroid formation or increased cholesterol oxidation. Compounds that increased the rate of cholesterol oxidation also inhibited steroid formation. Studies on kidney mitochondrial steroid formation, in the presence of 20:4n-6, showed a biphasic response. 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