Castration was previously demonstrated to result in an increase in liver alcohol dehydrogenase and in rates of ethanol elimination in male rats. In this study, the effect of dihydrotestosterone, which is a more potent androgen than testosterone in the rat, was determined on liver alcohol dehydrogenase and ethanol elimination in the castrated rat. Dihydrotestosterone was found to be a substrate of liver alcohol dehydrogenase in the reductive direction and a competitive inhibitor of ethanol oxidation by the enzyme. Also, the administration of a single dose of dihydrotestosterone inhibited liver alcohol dehydrogenase 4 hr after the injection, but this effect was not persistent at later intervals following injection. This transient in uiuo inhibition of liver alcohol dehydrogenase was associated with a delay in ethanol elimination. The microsomal ethanol-oxidizing enzyme system was found to play no role in the changes in ethanol elimination observed after castration and dihydrotestosterone administration since its activity remained unchanged. These studies provide further evidence of an effect of androgenic steroids on liver alcohol dehydrogenase activity and ethanol metabolism.
Castration results in an increase in liver alcohol dehy-These findings suggest that the activity of liver alcohol drogenase activity in male rats (1-3). The enhanced dehydrogenase is rate-limiting in ethanol elimination. enzyme activity in the castrated animals was decreased However, these studies did not include assessment of the by the administration of testosterone for 6 days in one possible role of the activity of the microsomal ethanolstudy (2) and totally suppressed after implantation of a oxidizing system. capsule of testosterone for 7 weeks in another study (1).
The purpose of this study was to determine the effects Furthermore, more recently, Cicero et al. (3) observed of dihydrotestosterone and other androgenic steroids on return of the enhanced activity to control levels 16 to 24 liver alcohol dehydrogenase activity and ethanol elimihr after injection of testosterone. These results suggested nation in the castrated rat. that testosterone or one of its metabolites was a direct inhibitor of the enzyme, however, no effect of either MATERIALS AND METHODS testosterone or dihydrotestosterone on liver alcohol de-Pregnenolone, 17a-hydroxypregnenolone, dehydroehydrogenase was demonstrated in vitro (3). The in vivo piandrosterone, A5-androstenediol, progesterone, l7a-hyeffect of dihydrotestosterone, which is derived from pe-droxyprogesterone, androstenedione, testosterone, and ripheral conversion of testosterone, and is a more potent dihydrotestosterone were obtained from Sigma Chemical androgen than testosterone in bioassays in the rat (41, Company, St. Louis, Mo. was not tested. Indeed, the delay in in vivo inhibition of the enzyme of 16 to 24 hr after administration of testos-ANIMALS AND TREATMENTS terone suggests that a metabolite such as dihydrotestos-Male Sprai+e-Dawley rats, initially weighing between terone may be the inhibitory compound. The rate of 100 and 120 gm (4 to 5 weeks of age), were kept in ethanol elimination has been found to change in associ-separate wire mesh cages in a room at a controlled ation with changes in liver alcohol dehydrogenase activ-temperature of 20ยฐC with light/dark cycles alternating ity, increasing after castration (1-3), and decreasing back every 12 hr. They \l:. . Tere provided water and Purina chow to normal Values after teSt0SterOne administration (1, 3). ad libitum. Castration was performed under ether anesthesia, while control animals had a sham surgical procedure consisting of dissection of the scrotum and manipulation of the testes with forceps. The animals were used 10 days after surgery. To determine the effects of testosterone and dihydrotestosterone on liver alcohol dehYdr0genase in vivo, these steroids were injected in a single