The commonly used
imidazole fungicide
prochloraz was tested for antiandrogenic effects in vitro and in vivo.
Prochloraz, but not the metabolites 2,4,6-trichlorophenoxyacetic
acid or
2,4,6-trichlorophenol, inhibited the R1881-induced response in an
androgen receptor reporter gene assay. In the Hershberger assay,
prochloraz exposure at all dose levels (50, 100, and 200 mg/kg) given orally to castrated
testosterone (T)-treated males markedly reduced weights of ventral prostate, seminal vesicles, musc. levator ani/bulbocavernosus, and bulbourethral gland. These effects were accompanied by an increase in LH and a reduction of the T(4) and TSH level. The effects on seminal vesicles, LH, T(4), and TSH were also evident in intact
prochloraz-exposed young adult rats.
Body weights were unaffected whereas liver weights were increased in
prochloraz-treated animals. Changes in
androgen-regulated gene expression were determined in ventral prostates by real-time RT-PCR. A pronounced decrease of ornithin
decarboxylase and PBP C3
mRNA levels was observed for both
prochloraz and
flutamide. These results indicate that
prochloraz antagonizes the peripheral
androgen receptors resulting in decreased growth of
androgen-dependent tissues and that it antagonizes central
androgen receptors blocking the negative feed-back mechanism of
testosterone resulting in increased LH secretion from the pituitary. The antiandrogenic effects of
prochloraz were in many ways qualitatively comparable, although weaker, to the effects of
flutamide. However, differential effects on levels of FSH, T(4), and TSH indicate that other modes of action apart from the pure AR antagonism might play a role in vivo.