Ketoconazole

Several fungicides inhibit fungal membrane synthesis and growth by inhibiting specific cytochrome P450 enzymes, especially 14a-demethylation of lanosterol in the sterol pathways. The process of steroidogenesis is sufficiently conserved that these chemicals also inhibit mammalian steroidogenesis. In general, however, at relatively high concentrations these fungicides are nonspecific inhibitors of CYP450 enzymes. Hence, effects in vertebrates may not be limited to the reproductive system and include adrenal and liver steroid metabolism and ecdysteroid synthesis in invertebrates.

Goldman et al. [190] produced male PH in rats with inhibitors of steroid 17a-hydroxylase and C17-20 lyase. Developmental alterations can also be obtained from in utero treatment with drugs that inhibit 5a-reductase, which is not a P450 enzyme, blocking the conversion of testosterone to DHT [191,192]. The antifungal imidazole derivative, ketoconazole, inhibits various enzymes which belong to the cytochrome-P450-dependent mono-oxygenases in rodents and humans such as side chain cleavage of cholesterol, 11^-hydroxylase in the adrenal, and 17a-hydroxylase and C17-20 lyase in rat and human testes. For example, human testicular mono-oxygenase activities in vitro are reduced by 50% by 3.1 |imol/l ketoconazole. Schurmeyer and Nieschlag [193] demonstrated that ketoconazole and other imidazole fungicides inhibited testosterone production in males, while Pepper et al. [194] reported that ketoconazole was useful in the treatment of ovarian hyperandrogenism in women. Ketoconazole also has been shown to alter hepatic testosterone metabolism [195]. Four hours after male CD-1 mice were orally treated with ketoconazole from 0 to 160 mg/kg, serum testosterone levels, gonadal testosterone production, and hepatic testosterone hydroxylase activities were decreased in a dose-related manner.

We found that administration of ketoconazole by gavage from GD 14 in the rat at 100 mg/kg/day leads to reduced maternal weight gain and whole litter loss within a few days of the initiation of treatment [115]. These effects are consistent with the ability of this fungicide to inhibit progesterone synthesis. When the dosage level of ketoconazole was lowered to 0, 12.5, 25, or 50 mg/kg/day from GD 14 to PND 3, treatment delayed the onset of parturition by as much as three days and reduced the numbers of live pups at all but the lowest dosage level. Surviving male pups in the 12.5 and 25 mg/kg/day dose groups (there was only one pup at 50 mg/kg/day) did not display any indication of being demas-culinized or feminized [115].

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