Estrogen and androgen receptor status in hepatocellular hypertrophy induced by phenobarbital, clofibrate, and piperonyl butoxide in F344 rats.

The present study examined hepatic estrogen receptor (ER) and androgen receptor (AR) levels as well as estrogen-signaling status in a model of rat hepatic hypertrophy induced by phenobarbital (PB), chlofibrate (CF), or piperonyl butoxide (PBO). Male F344 rats were fed with PB at 2,500 ppm, CF at 2,500 ppm, and PBO at 20,000 ppm for 3 days, 4 weeks, and 13 weeks. CF and PBO induced diffuse hypertrophy, while centrilobular hypertrophy was observed with PB administration. The levels of mRNA for ERα, AR and leukemia inhibitory factor receptor (LIFR) which was found to be estrogen responsive in the present study, were determined by quantitative RT-PCR. In the CF and PBO groups, ERα mRNA expression was reduced, and consequently, the expression of a responsive gene, LIFR, was also decreased, while PB had no effect on ER mRNA levels. AR mRNA expression decreased in all the treated groups, but reduction was persistent only in PB group. Recently, LIFR was identified as a tumor suppressor gene in human HCC. Thus, LIFR may be one of the key mediators of hepatic carcinogenesis induced by CF and PBO, but PB appears to act via different mechanisms.