Prevention of c-Jun/activator protein-1 activation and microsomal epoxide hydrolase induction in the rat liver by cysteine during protein-calorie malnutrition

Protein-calorie malnutrition (PCM), a major global health problem, arises d uring protein and/or energy deficit due to disease and nutritional inadequa cy. To date, cellular adaptive responses and gene expression associated wit h PCM remain poorly understood. In view of the primary role of the liver in energy conversion, the present study was designed to investigate changes i n hepatic morphology and molecular alterations during PCM. PCM caused marke d decreases in the cytoplasmic eosinophilic content and nuclear shrinkage i n the hepatocytes with a decrease in glutathione content. The nuclear activ ator protein-1 (AP-1) complex was activated in the liver of PCM rats. AP-1- binding activity of nuclear extracts produced from PCM rats was reduced by the presence of anti-c-Jun antibody. Microsomal epoxide hydrolase (mEH), a phase II detoxifying enzyme, was 4-fold induced, with a 20-fold increase in the mRNA level during PCM. In contrast to the PCM-induced changes in hepat ic morphology, PCM rats supplemented with cysteine showed an increase in th e GSH level and well-preserved hepatic structures with mild fat degeneratio n. Cysteine supplementation inhibited the activation of AP-1 and the induct ion of mEH in PCM rats. These results provided evidence: (i) that PCM alter s liver morphology with a decrease in the glutathione level; (ii) that cyst eine may serve as a key element responsible for preserving hepatic morpholo gy and maintaining the glutathione level; and (iii) that cysteine was activ e in preventing the activation of AP-1 and mEH induction in the liver durin g PCM. (C) 2000 Elsevier Science Inc. All rights reserved.