Spironolactone and Testicular Cytochrome P-450: Decreased Testosterone Formation inSeveral Species and Changes in Hepatic Drug Metabolism1

The daily administration of spironolactone caused a 40–90% decrease in the level of microsomal cytochrome P-450 in the testes of rat, guinea pig, rabbit, mouse and dog, but no reduction was detected in the amount of cytochrome b5. The loss of microsomal cytochrome P-450 was concomitant with a similar loss of both the microsomal heme associated with cytochrome P-450 and the activity of the microsomal 17α-hydroxylase. In contrast to its effects on the 17α-hydroxylase, spironolactone administration slightly increased the enzyme activity of the microsomal 17β-dehydrogenase. The extent of the destruction of cytochrome P-450 by spironolactone was dependent upon the dosegiven and upon the duration of the treatment. The decline in androgen formation in the testis resulted in a 30–35% decrease in the activity ofhepatic 3,4-benzpyrene hydroxylase in the rat, but an 80% increase in the guinea pig. The decrease inthe 3,4-benzpyrene hydroxylase activity in the rat could be prevented by the administration ofandrogens, such as 17-methyltestosterone. In contrast to the decline in 3,4-benzpyrene hydroxylaseactivity in the male rat, spironolactone administration enhanced the activity of both ethylmorphine N-demethylase and NADPH cytochrome c reductase in the liver of the male rat and guinea pig. Other steroids such as progesterone and testosterone, given at a dose similar to that of spironolactone, also lowered the content of cytochrome P-450 in the testis. However, in contrast to the rapid destruction of cytochrome P-450 by spironolactone, the decrease in the level ofcytochrome P-450 bytestosterone or progesterone is probably caused by a decline in the level of LHresulting from asteroidfeedback inhibition on the release of LH from the pituitary gland. (Endocrinology94: 1628, 1974)