Impaired mitochondrial oxidative energy metabolism following paracetamol‐induced hepatotoxicity in the rat

Abstract

1 Effects of paracetamol treatment in vivo at subtoxic (375mgkg-' body weight) and toxic (750 mg kg-1 body weight) doses on energy metabolism in rat liver mitochondria were examined. 2 Paracetamol treatment resulted in a significant loss in body weights without affecting the liver protein contents. Toxic doses, however, resulted in 21% decrease in the yield of mitochondrial proteins.3 Subtoxic doses of paracetamol did not, in general, affect the respiratory parameters in the liver mitochondria except in the case of succinate where both the state 3 respiration and the ADPphosphorylation rates increased by 28%. 4 Toxic doses of paracetamol caused 25 to 47% decrease in the state 3 respiration rates depending on the substrate used. ADP/O ratios also decreased significantly with pyruvate + malate and succinate as the substrates. Consequently, ADP-phosphorylation was impaired significantly from 20 to 63%. 5 Subtoxic doses of paracetamol resulted in increased contents of cytochrome c + cl while the toxic doses caused lowering of the cytochromes aa3 and b contents. 6 Glutamate and succinate dehydrogenase activities decreased in both the experimental groups while Mg2 +-ATPase activity was impaired only after toxic dose-treatment. 7 The results show that toxic doses of paracetamol result in impaired energy coupling in the liver mitochondria. Effects of subtoxic doses were also demonstrable in terms of impaired dehydrogenases activities.

Prevention of paracetamol‐induced hepatic damage in rats by picroliv, the standardized active fraction from Picrorhiza kurroa

“…An increase in the activity of y-glutamyl transpeptidase and decrease in 5'-nucleotidase (marker enzymes of plasma membrane) suggest that paracetamol or its reactive metabolite acts at the plasma membrane which is in agreement with report of Corcoran et al (1987) that integrity of the plasma membrane of hepatocytes decreased following treatment with paracetamol. Inhibition in the mitochondrial respiration (Meyers et al, 1988) and mitochondrial enzymes (Katyare and Satav, 1989) by paracetamol have also been reported. The present results suggest that in addition, paracetamol acts on hepatic microsomes and mitochondria as indicated by depletion of cytochrome Pd5", glucose-6-phosphatase and succinate dehydrogenase.…”

Ethanol feeding enhances age-related deterioration of the rat hepatic mitochondrion

“…If impaired mitochondrial function represents an underlying component of cellular aging, a concept proposed by a number of researchers, then ethanol feeding would be expected to contribute to the aging process. In this regard, ethanol may not be alone as a number of xenobiotics [e.g., steroids, analgesics (11,30)] and physiological conditions [e.g., lung cancer and pancreatitis (26,34)], have been shown to affect liver mitochondria in a similarly deleterious manner. Aging should therefore be viewed as an underlying disease state that can be impinged upon, both positively and negatively, by a multitude of external and internal cellular insults.…”

Effect of dehydroepiandrosterone (DHEA) treatment on oxidative energy metabolism in rat liver and brain mitochondria. A dose–response study

“…State 3 respiration rates initiated by the addition of 80-200 nmol of ADP and state 4 respiration rates ensuing after the depletion of added ADP were recorded. Calculations of ADP/O ratio and ADP phosphorylation rates were as described previously [21,22].…”