Assessment of hepatic function in rabbits with steroid-induced cholestatic liver injury

Methyltestosterone (MT) or ethinyl estradiol (EE) was administered to adult rabbits for 20 weeks beginning with initial daily doses of 0.4 mg/kg MT and 0.015 mg/kg EE for three weeks, then these dosages were doubled at 3-week intervals to a maximum dosages 6.4 mg/kg and 0.24 mg/kg, respectively. Within 2 weeks, the serum gamma-glutamyltransferase activity of MT and EE treated rabbits was significantly greater than controls and increased progressively throughout the treatment period. Aspartate aminotransferase activity was also increased at 2 weeks and remained so for 17 weeks. Serum alkaline phosphatase was elevated at 2 weeks but thereafter was normal indicating that this enzyme is of no value in detecting steroid-induced hepatic dysfunction. Elevated serum bile acid concentration and prolonged BSP clearance indicated marked hepatic excretory dysfunction at higher dose levels. Histologic abnormalities were observed in the livers of both MT and EE treated rabbits. These lesions were more severe in the EE group in which there was marked bile duct proliferation, mononuclear cell infiltration of portal areas, and perilobular fibrosis. The studies indicate that the rabbit is susceptible to development of hepatic injury when receiving 17 alpha-alkyl substituted steroids and may be a useful animal model for investigations of the pathogenesis of steroid-induced cholestatic liver injury.