EFFECTS OF ETHANOL ON MITOGEN-ACTIVATED PROTEIN-KINASE AND STRESS-ACTIVATED PROTEIN-KINASE CASCADES IN NORMAL AND REGENERATING LIVER

To understand the mechanisms by which ethanol inhibits hepatocyte prol iferation, we studied the effects of ethanol on p42/44 mitogen-activat ed protein kinase (MAPK), p38 mitogen-activated protein kinase (g38 MA PK) and c-Jun N-terminal kinase (JNK) in normal and regenerating rat l iver, Treatment of rat hepatocytes with 100 mM ethanol in vitro for 16 h prolonged the activation of p42/44 MAPK and p38 MAPK induced by var ious agonists, Such treatment also increased basal JNK activity, but d id not potentiate or prolong agonist-induced JNK activation. Ethanol p otentiation of the activation of p42/44 MAPK was abolished by pertussi s toxin. In contrast, chronic ethanol consumption irt vivo inhibited t he activation of p42/44 MAPK, F38 MAPK and JNK induced either by parti al hepatectomy or by various agonists. However, both acute and chronic ethanol inhibited hepatocyte proliferation induced by insulin and epi dermal growth factor. A selective inhibitor of p42/44 MAPK partially p revented the inhibition of hepatocyte proliferation caused by acute? b ut not by chronic, ethanol exposure, whereas a selective inhibitor of p38 MAPK further inhibited hepatocyte proliferation under both conditi ons. These data suggest that acute and chronic ethanol inhibit hepatoc yte proliferation by different mechanisms. The effect of acute ethanol may be related to the prolongation of p42/44 MAPK activation, whereas inhibition of hepatocyte proliferation by chronic ethanol may be due to inhibition of p38 MAPK activation.