The contribution of hepatic inactivation of testosterone to the lowering of serum testosterone levels by ketoconazole

Citation
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
Citations number
37
Categorie Soggetti
Pharmacology & Toxicology
Journal title
TOXICOLOGICAL SCIENCES
ISSN journal
10966080 → ACNP
Volume
54
Issue
1
Year of publication
2000
Pages
128 - 137
Database
ISI
SICI code
1096-6080(200003)54:1<128:TCOHIO>2.0.ZU;2-F
Abstract
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.