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Titolo:
The contribution of hepatic inactivation of testosterone to the lowering of serum testosterone levels by ketoconazole
Autore:
Wilson, VS; LeBlanc, GA;
Indirizzi:
N Carolina State Univ, Dept Toxicol, Raleigh, NC 27695 USA N Carolina State Univ Raleigh NC USA 27695 Toxicol, Raleigh, NC 27695 USA
Titolo Testata:
TOXICOLOGICAL SCIENCES
fascicolo: 1, volume: 54, anno: 2000,
pagine: 128 - 137
SICI:
1096-6080(200003)54:1<128:TCOHIO>2.0.ZU;2-F
Fonte:
ISI
Lingua:
ENG
Soggetto:
PLASMA STEROID-LEVELS; POLYCHLORINATED-BIPHENYLS; HYDROXYLASE-ACTIVITIES; CATOSTOMUS-COMMERSONI; HORMONAL-REGULATION; MICROSOMAL-ENZYMES; MILL EFFLUENT; RAT; METABOLISM; CYTOCHROME-P-450;
Keywords:
androgen disruption; hepatic biotransformation; ketoconazole; mice; testosterone;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
37
Recensione:
Indirizzi per estratti:
Indirizzo: LeBlanc, GA N Carolina State Univ, Dept Toxicol, Box 7633, Raleigh, NC 27695 USA N Carolina State Univ Box 7633 Raleigh NC USA 27695 27695 USA
Citazione:
V.S. Wilson e G.A. 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

Abstract

Hepatic biotransformation processes can be modulated by chemical exposure and these alterations can impact the biotransformation of endogenous substrates. Furthermore, chemically mediated alterations in the biotransformationof endogenous steroid hormones have been implicated as a mechanism by which steroid hormone homeostasis can be disrupted. The fungicide ketoconazole has been shown to lower serum testosterone levels and alter both gonadal synthesis and hepatic inactivation of testosterone. The present study examined whether the effects of ketoconazole on the hepatic biotransformation of testosterone contribute to its lowering of serum testosterone levels. Results also were used to validate further the use of the androgen-regulated hepatic testosterone 6 alpha/15 alpha-hydroxylase ratio as an indicator of androgen status. Male CD-1 mice were fed from 0 to 160 mg/kg ketoconazole in honey. Four h after the initial treatment, serum testosterone levels, gonadaltestosterone secretion, and hepatic testosterone hydroxylase activity decreased, and the hepatic testosterone 6 alpha/15 alpha-hydroxylase ratio increased in a dose-dependent manner. Immunoblot analysis indicated that the transient decline in hepatic biotransformation was not due to reduced P450 protein levels. Rather, hepatic testosterone biotransformation activities were found to be differentially susceptible to direct inhibition by ketoconazole. Differential inhibition was also responsible for the increase seen in the 6 alpha/15 alpha-hydroxylase ratio. The changes in serum testosterone levels could be explained by decreased gonadal synthesis of testosterone and were not impacted by decreased hepatic biotransformation of testosterone. These results demonstrate that changes in the hepatic hydroxylation of testosterone by ketoconazole, and perhaps other chemicals, have little or no influence serum testosterone levels.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 14/08/20 alle ore 17:08:27