Acatalasemia is caused by genetic defect in the catalase gene. Human achatalasemia patients are able to scavenge physiological hydrogen peroxide but are vulnerable to exogenous oxidative stress. In the present study, we used an acetaminophen-induced hepatotoxicity model in acatalasemic mice to explore this vulnerability. Interestingly, the acetaminophen-induced decrease in total glutathione levels was more prolonged in acatalasemic mice. While the subunits of glutamate-cysteine ligase, a glutathione synthase enzyme, were increased by acetaminophen in the liver of wild-type mice, their expression was lower and was further reduced by acetaminophen in acatalasemic mice. This feature was also observed in immortalized hepatocytes derived from the livers of these mice. However, when catalase was knocked down in HepG2 cells, a cultured human liver cell line, the expression of glutamate-cysteine ligase subunits was increased, suggesting that the low expression of glutamate-cysteine ligase subunits in acatalasemia may be due to other mechanism than catalase deficiency. Therefore, when other factors were investigated, it was found that transforming growth factor-β1 was up-regulated by acetaminophen in the liver of acatalasemic mice, which may inhibit the expression of glutamate-cysteine ligase subunits. The results of this study suggest a new toxic mechanism of acetaminophen-induced liver injury in patients with acatalasemia.
Keywords: Acatalasemia; Acetaminophen; Catalase; Liver injury; Oxidative stress.
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