Effect of alpha-asarone and a derivative on lipids, bile flow and Na+/K+-ATPase in ethinyl estradiol-induced cholestasis in the rat.

摘要

Administration of ethinyl estradiol (EE), a widely used component of oral contraceptives, has been associated with impairment of bile flow and the capacity to excrete organic anions in man and experimental animals. alpha-Asarone (2,4,5-trimethoxypropenylbenzene) and 2-methoxy-4-(2-propenyl) phenoxyacetic acid (MPPA) have shown hypolipidemic effects. In addition to these effects, we decided to evaluate the properties of these compounds on EE-induced cholestasis. Wistar male rats were injected subcutaneously with 10 mg/kg of EE for 5 days; simultaneously, alpha-asarone or MPPA were also administered and appropriate controls were performed. alpha-asarone and MPPA decreased plasma and bile cholesterol. EE diminished triglycerides total, low-density lipoprotein, high-density lipoprotein and bile cholesterol. MPPA further decreased these lipid parameters. Alkaline phosphatase (an enzyme marker of cholestasis) was increased after administration of EE, but this effect was prevented significantly by alpha-asarone or MPPA administration. Bile flow was importantly decreased by EE and increased by alpha-asarone alone. Furthermore, alpha-asarone or MPPA preserved the normal bile flow in EE-treated rats. EE inhibited the activity of the Na(+)/K(+)-ATPase, while both alpha-asarone and MPPA preserved this enzyme activity. Na(+)/K(+)-ATPase is involved in Na(+)-coupled uptake of bile acids into hepatocytes and, therefore, ultimately is the driving force for the generation of bile flow. Therefore, the anticholestatic effects of alpha-asarone and MPPA, described herein by the first time, may be due to its ability to preserve ATPase activity. This enzyme is negatively regulated by membrane cholesterol, thus the hypolipidemic effects of the compounds tested may be responsible for Na(+)/K(+)-ATPase activity and bile flow maintenance.