HEPATOPROTECTIVE EFFECTS OF CYPROTERONE ACETATE IN MICE; MINIMAL ROLE OF METALLOTHIONEIN

Abstract

Previously, we reported that the antiandrogen cyproterone acetate (CA) modifies cadmium (Cd) distribution and metallothionein (MT) induction in mice given a non-toxic dose of Cd (10 w mol Cd/kg, sc). We have also observed that CA pretreatment will reduce Cd toxicity in in vitro systems. Thus, since the liver is a primary target of acute Cd toxicity, the effects of CA pretreatment on the acute hepatotoxicity of Cd in vivo were studied in male C57 mice. Mice were pretreated with CA (10 mg/kg, sc, at - 48, - 24, and 0 h) prior to Cd (35 or 45 w mol Cd/kg, at 0 h). Cd alone (35 or 45 w mol Cd/kg) induced significant increases in serum alanine aminotransferase (ALT) activity, indicative of hepatotoxicity, 24 h after injection. However, CA pretreatment either prevented (at 35 w mol Cd/kg) or significantly reduced (at 45 w mol Cd/kg) Cd-induced increases in serum ALT. Based on serum creatinine levels, Cd alone was not acutely nephrotoxic. Thus, CA pretreatment substantially reduced the hepatotoxic effects of Cd. CA pretreatment had no effect on hepatic Cd levels 24 h after Cd exposure. The hepatic levels of zinc, a metal known to antagonize Cd toxicity, were modestly altered by CA pretreatment, but not in a consistent fashion. Cd alone markedly increased hepatic MT, a metal-binding protein often associated with tolerance to Cd, 24 h after exposure. CA pretreatment alone did not alter hepatic MT levels and pretreatment with CA before Cd did not alter hepatic levels of MT compared to Cd alone 24 h after injection of the metal. To further examine the tolerance to Cd induced by CA, the effects of CA pretreatment on hepatic Cd levels at early stages were investigated. Hepatic Cd levels were significantly decreased by CA pretreatment 8 h after Cd treatment and returned to control levels by 16 h. These results indicate that CA can substantially reduce the hepatotoxic effects of Cd in C57 mice without activating MT synthesis. The early decreases in liver Cd content may be critical to decreasing the adverse effect of Cd in the liver. Thus, it appears CA induces tolerance to Cd through altered biokinetics and in a manner not involving the MT system.