Malic enzyme and glucose 6-phosphate dehydrogenase gene expression increases in rat liver cirrhogenesis

Abstract

Summary The cirrhogenic ability of thioacetamide has been used to induce a model of chronic generalized liver disease that resembles the preneoplastic state of human fibrosis. Malic enzyme (ME) and glucose-6-phosphate dehydrogenase (G6PDH) are two cytosolic NADPHgenerating enzymes; their activities significantly increased in liver when macronodular cirrhosis was induced by long-term thioacetamide administration to rats. The progressive increase in G6PDH and ME activities during the cirrhogenic process is parallel to the induction in gene expression of both enzymes 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 state could be involved. A relationship between the extent of G6PD and ME gene expression and oxidative stress generated by the oxidative metabolism of thioacetamide is proposed as the hepatic concentration of malondialdehyde, a metabolite derived from lipid peroxidation, underwent a progressive and significant enhancement during thioacetamide-induced cirrhogenesis. These results led us to suggest that the enhanced activities of G6PDH and ME might be related to microsomal mechanisms of detoxification as well as to the maintenance of the cellular redox state. Furthermore, the noticeable increase in the hepatocyte population involved in DNA replication parallel to G6PDH activity suggests that G6PDH, through ribose-5-phosphate, might also be involved in the processes of DNA synthesis and repair.

Mechanism Responsible for the Decreased Hepatic NADPH Generation Rate in Rats with Bilateral Ureter Ligation-Induced Renal Failure

“…15) In addition, G-6-PD activity was increased in rats with liver injury produced by dimethylnitrosamine.…”

The power to reduce: pyridine nucleotides – small molecules with a multitude of functions

“…Both activities are not essential for cellular NADPH maintenance. However, cytosolic ME activity is increased in rat liver cirrhogenesis [88] and affected in acute hepatic injury [89], presumably by providing NADPH for detoxification reactions. Like IDPc, cytosolic ME is also not up-regulated in mouse cells deleted for G6PD [67].…”

Co-administration of cyclosporine A alleviates thioacetamide-induced liver injury

“…TAA undergoes an extensive metabolism to acetamide shortly after administration and to the hepatotoxic metabolite TAA-S-oxide by the mixed function oxidase system [2][3][4] . Free radical-mediated lipid peroxidation contributes to the development of TAAinduced liver fibrosis [5,6] . In chronic TAA intoxication, substantial liver fibrosis and prominent regenerative nodules develop after 3 mo of TAA administration and are associated with portal hypertension and the hyperdynamic circulation characteristic of liver cirrhosis [7] .…”