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

Abstract

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 b 5 . 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 17a-hydroxylase. In contrast to its effects on the 17a-hydroxylase, spironolactone administration slightly increased the enzyme activity of the microsomal 17/3-dehydrogenase. The extent of the destruction of cytochrome P-450 by spironolactone was dependent upon the dose given and upon the duration of the treatment.The decline in androgen formation in the testis resulted in a 30-35% decrease in the activity of hepatic 3,4-benzpyrene hydroxylase in the rat, but an 80% increase in the guinea pig. The decrease in the 3,4-benzpyrene hydroxylase activity in the rat could be prevented by the administration of androgens, such as 17-methyltestosterone. In contrast to the decline in 3,4-benzpyrene hydroxylase activity 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 of cytochrome P-450 by testosterone or progesterone is probably caused by a decline in the level of LH resulting from a steroidfeedback inhibition on the release of LH from the pituitary gland. (Endocrinology 94: 1628(Endocrinology 94: , 1974 V ARIOUS steroids including spironolgjetone have been reported by Selye (1) to protect rats against the toxic effects of a number of foreign compounds such as drugs, carcinogens, and insecticides. Subsequent studies have revealed that the protective action of these steroids is associated with an increased clearance of the toxicants from the blood rather than an increased tolerance to the toxicant (2). Moreover, Solymoss et al. (3), Feller and Gerald (4), and Stripp et al. (5) have demonstrated that the mode of protection afforded by spironolactone results from the stimulation of drug metabolism by the mixed function oxidases in liver.

Adrenal independence of fluid and electrolyte reabsorption in the ductuli efferentes testis of the rat

“…The absence of an effect of adrenalectomy or spironolactone treatment on the masses of the testis and accessory glands in this study is in agreement with published reports in the rat which show that adrenalectomy (Feek, Tuzi & Edwards, 1989) and spironolactone treatment (Menard, Stripp & Gilette, 1974) do not affect chronic circulating testosterone levels, or mass of the testes or seminal vesicles (Wong & Lee, 1982). Turner & Cesarini (1983), however, did report a small but significant effect on seminal vesicle (but not testis) weight.…”

Effect of thiazide drug compound on the testicular protein and cholesterol contents of albino rat

“…In the present study, the total protein content decrease in the testes of albino rats may be due to the side effects of thiazide drug compound. In the present study it has also been reported by Menard (1974). It is likely that the lipoprotein and protein contents decreases by the adverse effect of thiazide and is mainly characterized by degradation of microsomal cytochrome p-450; while Fanestil (1997) reported in the kidney the metabolic influence of drug hydrochlorothiazide.…”

Effect of spironolactone and potassium canrenoate on cytosolic and nuclear androgen and estrogen receptors of rat liver

“…There have been many reports addressing the mechanism of this action. Menard et al (22) demonstrated, in several species, that spironolactone treatment decreases the microsomal cytochrome P 450 content of the testes and reduces the activity of 17-hydroxylase, an enzyme necessary for testosterone synthesis. In women treated with spironolactone to reduce hirsutism, this drug has been shown to increase testosterone clearance (23) and decrease genital skin fibroblast steroid 5α reductase (24).…”

“…Different explanations have been offered for the hormonal changes induced by these drugs, and spironolactone in particular. These include reduction in testosterone synthesis (22,23), increase in testosterone clearance (23), reduction of 5α-reductase activity (24), and interference with AR activity (25). To date, no report has defined the effects of these drugs on the sex hormone receptor state of the liver.…”