Functional, biochemical, and morphological hepatobiliary effects in rats chronically exposed to a steroidal antiandrogen.
Yellow-brown deposits in intrahepatic bile ducts and portal macrophages were observed for male, but not female, Sprague- Dawley rats fed zanoterone, a steroidal antiandrogen, for >=3 months. The lesion did not affect biliary canaliculi and was associated with changes of biliary epithelium, portal chronic inflammation, and bile duct proliferation. Deposit formation was assumed to be related to a gender-related anomaly in bile composition and/or flow. Therefore, the pathogenesis of the lesion was investigated in male, female, and orchiectomized rat. Hepatobiliary structure and function were evaluated after 3 months of treatment and 3 months of reversibility. Drug biliary disposition was evaluated at 3 months. Sulfobromophthalein clearance, bile flow, and plasma concentration and biliary excretion rate of cholesterol were increased at the end of the treatment phase without significant sex-related differences. These effects are consistent with the hepatic enzyme induction potential of the drug, were accompanied by perivenous hepatocellular hypertrophy and increased liver weights, and were no longer observed at the end of the recovery phase. Histomorphologic evidence of cholestasis was observed for most intact and orchiectomized males, the lesion being slightly less pronounced for the latter. Deposits were present at the end of the recovery phase, but were confined to macrophages in all but one case. The lesion differed from a protoporphyria, or precipitates of bile pigments, cholesterol, or proteins. The drug was extensively metabolized with major gender-related differences. Glucuronides of a 16- hydroxy- and another unidentified metabolite were the major metabolites found in bile of males, while a 15-hydroxy-glucuronide was the major metabolite for females. The concentration and biliary excretion of the 16-hydroxy- glucuronide markedly increased after chronic exposure. A possible explanation for pigment deposition in males is that the drug is converted to a metabolite(s) which is excreted at a rate beyond the solubilization potential of bile and, therefore, precipitates in bile ducts.
Descotes
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Department of Drug Safety Assessment, Sanofi Recherche, Longvic-les-Dijion, France.
Osman
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Gallas
J F
JF
Penacchio
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Moreau
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D000726:Androgen Antagonists / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D001646:Bile / Q000737:chemistry / Q000502:physiology; D001647:Bile Acids and Salts / Q000378:metabolism; D001659:Biliary Tract / Q000187:drug effects* / Q000473:pathology; D001835:Body Weight / Q000187:drug effects; D002780:Cholestasis, Intrahepatic / Q000139:chemically induced; D002784:Cholesterol / Q000097:blood; D004435:Eating / Q000187:drug effects; D005260:Female; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008111:Liver Function Tests; D008297:Male; D009919:Orchiectomy; D011278:Pregnanes / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D011720:Pyrazoles / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012727:Sex Characteristics; D013448:Sulfobromophthalein
D000726:Androgen Antagonists; D001647:Bile Acids and Salts; D011278:Pregnanes; D011720:Pyrazoles; D013448:Sulfobromophthalein; D002784:Cholesterol; C060492:zanoterone