Vs. Wilson et Ga. Leblanc, The contribution of hepatic inactivation of testosterone to the lowering of serum testosterone levels by ketoconazole, TOXICOL SCI, 54(1), 2000, pp. 128-137
Hepatic biotransformation processes can be modulated by chemical exposure a
nd these alterations can impact the biotransformation of endogenous substra
tes. Furthermore, chemically mediated alterations in the biotransformation
of endogenous steroid hormones have been implicated as a mechanism by which
steroid hormone homeostasis can be disrupted. The fungicide ketoconazole h
as been shown to lower serum testosterone levels and alter both gonadal syn
thesis and hepatic inactivation of testosterone. The present study examined
whether the effects of ketoconazole on the hepatic biotransformation of te
stosterone contribute to its lowering of serum testosterone levels. Results
also were used to validate further the use of the androgen-regulated hepat
ic testosterone 6 alpha/15 alpha-hydroxylase ratio as an indicator of andro
gen status. Male CD-1 mice were fed from 0 to 160 mg/kg ketoconazole in hon
ey. Four h after the initial treatment, serum testosterone levels, gonadal
testosterone secretion, and hepatic testosterone hydroxylase activity decre
ased, and the hepatic testosterone 6 alpha/15 alpha-hydroxylase ratio incre
ased in a dose-dependent manner. Immunoblot analysis indicated that the tra
nsient decline in hepatic biotransformation was not due to reduced P450 pro
tein levels. Rather, hepatic testosterone biotransformation activities were
found to be differentially susceptible to direct inhibition by ketoconazol
e. Differential inhibition was also responsible for the increase seen in th
e 6 alpha/15 alpha-hydroxylase ratio. The changes in serum testosterone lev
els could be explained by decreased gonadal synthesis of testosterone and w
ere not impacted by decreased hepatic biotransformation of testosterone. Th
ese results demonstrate that changes in the hepatic hydroxylation of testos
terone by ketoconazole, and perhaps other chemicals, have little or no infl
uence serum testosterone levels.