Chronic alcoholic men often exhibit a spectrum of sexual dysfunction. These men are frequently hypogonadal and generally have low serum testosterone levels. Since sex hormones exert their influence at the cellular level by interactions with their highly specific hormone receptors, it is predictable that chronic alcohol exposure would alter androgen receptor status and thus the response of the cell to androgens. In a rat model, male rats fed alcohol demonstrate altered responses to androgens. As in human males, these animals have a significant reduction in serum testosterone, demonstrate reduced hepatic androgen receptor levels, and show a parallel reduction in activities of two hepatic androgen-responsive proteins. The research outlined in this proposal addresses the mechanisms for alcohol-induced alterations in sex steroid function by studying the regulation of one of these hepatic androgen-responsive proteins in detail. The protein to be studied is an unusual cytosolic male- and liver-specific protein which has estrogen binding activity (MEB).This MEB protein is the focus of our studies in a rat model of chronic alcohol feeding because: (1) it represents an excellent marker for androgen effects on the liver; (2) the activity of this protein is significantly reduced (50-70%) in the setting of chronic alcohol ingestion; (3) its estrogen binding activity suggests that it may play a role in estrogen homeostasis in the male; and (4) its reduction in alcohol-fed animals is concomitant with a rise in serum estradiol and an increase in the activity of an estrogen-responsive hepatic protein. To better study the role of MEB, we will purify this protein and generate antibodies to it. These antibodies will be used to elucidate the role of this protein, and its regulation in livers of normal and alcohol-fed male rats. Other later experiments will be performed to define the temporal relationship and the reversibility of alcohol-induced changes. The results of this research will provide a basis for understanding the mechanisms responsible for alterations in sex steroid function in the setting of chronic alcohol exposure. By use of such a rat model, we can identify factors which are essential for the regulation of androgen-responsive liver function, and thus may provide a basis for future studies in humans.
| Rao, K N; Elm, M S; Kelly, R H et al. (1997) Hepatic hyperplasia and cancer in rats: metabolic alterations associated with cell growth. Gastroenterology 113:238-48 |
| Eagon, P K; Chandar, N; Epley, M J et al. (1994) Di(2-ethylhexyl)phthalate-induced changes in liver estrogen metabolism and hyperplasia. Int J Cancer 58:736-43 |
| Eagon, P K; Elm, M S; Stafford, E A et al. (1994) Androgen receptor in human liver: characterization and quantitation in normal and diseased liver. Hepatology 19:92-100 |
