Chen J, Ishac E J, Dent P, Kunos G, Gao B
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298, USA.
Biochem J. 1998 Sep 15;334 ( Pt 3)(Pt 3):669-76. doi: 10.1042/bj3340669.
To understand the mechanisms by which ethanol inhibits hepatocyte proliferation, we studied the effects of ethanol on p42/44 mitogen-activated protein kinase (MAPK), p38 mitogen-activated protein kinase (p38 MAPK) and c-Jun N-terminal kinase (JNK) in normal and regenerating rat liver. 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 various agonists. Such treatment also increased basal JNK activity, but did not potentiate or prolong agonist-induced JNK activation. Ethanol potentiation of the activation of p42/44 MAPK was abolished by pertussis toxin. In contrast, chronic ethanol consumption in vivo inhibited the activation of p42/44 MAPK, p38 MAPK and JNK induced either by partial hepatectomy or by various agonists. However, both acute and chronic ethanol inhibited hepatocyte proliferation induced by insulin and epidermal growth factor. A selective inhibitor of p42/44 MAPK partially prevented the inhibition of hepatocyte proliferation caused by acute, but not by chronic, ethanol exposure, whereas a selective inhibitor of p38 MAPK further inhibited hepatocyte proliferation under both conditions. These data suggest that acute and chronic ethanol inhibit hepatocyte 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.
为了解乙醇抑制肝细胞增殖的机制，我们研究了乙醇对正常和再生大鼠肝脏中p42/44丝裂原活化蛋白激酶（MAPK）、p38丝裂原活化蛋白激酶（p38 MAPK）和c-Jun氨基末端激酶（JNK）的影响。体外以100 mM乙醇处理大鼠肝细胞16小时，可延长各种激动剂诱导的p42/44 MAPK和p38 MAPK的激活时间。这种处理还增加了基础JNK活性，但未增强或延长激动剂诱导的JNK激活。百日咳毒素可消除乙醇对p42/44 MAPK激活的增强作用。相反，体内长期摄入乙醇可抑制部分肝切除或各种激动剂诱导的p42/44 MAPK、p38 MAPK和JNK的激活。然而，急性和慢性乙醇均可抑制胰岛素和表皮生长因子诱导的肝细胞增殖。p42/44 MAPK的选择性抑制剂可部分阻止急性乙醇暴露（而非慢性乙醇暴露）所致的肝细胞增殖抑制，而p38 MAPK的选择性抑制剂在两种情况下均可进一步抑制肝细胞增殖。这些数据表明，急性和慢性乙醇通过不同机制抑制肝细胞增殖。急性乙醇的作用可能与p42/44 MAPK激活时间的延长有关，而慢性乙醇对肝细胞增殖的抑制可能是由于p38 MAPK激活的抑制。
