Effect of a low-protein diet on contraceptive steroid-induced cholestasis in rats

Female Sprague-Dawley rats were given daily oral doses of 2 combined oral contraceptive (OC) steroids, 17 alpha-ethinyl estradiol (EE2) and 19-norethisterone (NE), for a maximum of 8 weeks. A low-dose group of rats received 0.25 mg/kg EE2 and 2.50 mg/kg NE. A high-dose group was given weekly doubled doses until levels of 4 mg/kg EE2 and 40 mg/kg NE were reached. The rats were fed a low-protein (LP) (8%) diet starting 8 weeks before treatment with the OC and continuing throughout the study. Cholestatic liver injury, as measured by basal bile flow, bile acid secretion, and organic anion (bromosulfophthalein) excretion, could be induced in control rats receiving the LP diet alone. In control animals on a normal diet, steroid administration alone produced a marked dose-dependent cholestatic effect. However, the combination of a chronic LP diet with OC resulted in an ameliorating effect on the pathophysiology of bile secretion and hepatic excretory function. The histopathological adaptive changes induced by OC were absent when the LP diet was administered simultaneously. Thus, in the rat, mild protein malnutrition does not enhance the cholestatic effect of the steroids but rather protects the liver from cholestatic liver damage caused by an LP diet or OC administration alone.