MALIC ENZYME AND GLUCOSE-6-PHOSPHATE-DEHYDROGENASE GENE-EXPRESSION INCREASES IN RAT-LIVER CIRRHOGENESIS

The cirrhogenic ability of thioacetamide has been used to induce a mod el of chronic generalized liver disease that resembles the preneoplast ic state of human fibrosis. Malic enzyme (ME) and glucose-6-phosphate dehydrogenase (G6PDH) are two cytosolic NADPH-generating enzymes; thei r activities significantly increased in liver when macronodular cirrho sis was induced by long-term thioacetamide administration to rats. The progressive increase in G6PDH and ME activities during the cirrhogeni c process is parallel to the induction in gene expression of both enzy mes detected by the increase in their mRNAs. These data indicate that NADPH-consuming mechanisms such as the microsomal oxidizing system and the maintenance of the cell redox slate could be involved. A relation ship between the extent of G6PD and ME gene expression and oxidative s tress generated by the oxidative metabolism of thioacetamide is propos ed as the hepatic concentration of malondialdehyde, a metabolite deriv ed from lipid peroxidation, underwent a progressive and significant en hancement during thioacetamide-induced cirrhogenesis. These results le d us to suggest that the enhanced activities of G6PDH and ME might be related to microsomal mechanisms of detoxification as well as to the m aintenance of the cellular redox state. Furthermore, the noticeable in crease in the hepatocyte population involved in DNA replication parall el to G6PDH activity suggests that G6PDH, through ribose-5-phosphate, might also be involved in the processes of DNA synthesis and repair.