Downregulation of nuclear sex steroid receptor activity correlates with severity of alcoholic liver injury

Chronic ethanol ingestion in rats and humans results in significant alterat ions in sex steroid levels and expression of sex hormone-dependent phenotyp e. In this study, we used the intragastric feeding model in male rats to de termine hepatic sex hormone receptor activity under circumstances of chroni c ethanol exposure and differing degrees of liver injury induced by type of dietary fat. Pathological analysis and quantitation of hepatic androgen re ceptor (AR) and estrogen receptor (ER) activity, serum sex hormones, and se x hormone-responsive protein and mRNA expression were performed. The activi ty of the physiologically relevant nuclear form of both AR and ER was signi ficantly decreased with ethanol and correlated inversely with the severity of liver injury. Serum testosterone levels, as well as expression of an and rogen-dependent hepatic mRNA, were decreased by ethanol and progressive liv er injury. Serum estradiol increased with liver injury. We postulate that t hese changes in receptor activity may be due to the oxidative stress, reduc ed cellular energy, and/or altered cytokine milieu known to occur in this m odel.