Oxidative stress caused by a SOD1 deficiency ameliorates thioacetamide-triggered cell death via CYP2E1 inhibition but stimulates liver steatosis

Abstract

We investigated the responses of mice that are defective in the superoxide-scavenging enzyme SOD1 to thioacetamide (TAA)-induced hepatotoxicity. When a lethal dose of TAA (500 mg/kg) was intraperitoneally injected, the wild-type (WT) mice all died within 36 h, but all of the SOD1-knockout (KO) mice survived. Treatment with an SOD1 inhibitor rendered the WT mice resistant to TAA toxicity. To elucidate the mechanism responsible for this, we examined the acute effects of a sublethal dose of TAA (200 mg/kg) on the livers of WT and KO mice. The extent of TAA-induced liver damage was less in the KO mice, but, instead, lipogenesis was further advanced in the SOD1-KO livers. The levels of proteins modified with acetyllysine, a marker for TAA-mediated injury, were lower in the KO mice than the WT mice upon the TAA treatment. The KO mice, which were under oxidative stress per se, exhibited a lower CYP2E1 activity, and this appeared to result in a decrease in the production of reactive oxygen species (ROS) during TAA metabolism. Both cleaved ATF6, a transcriptional regulator that is activated by endoplasmic reticulum (ER) stress, and CHOP, a death signal mediator, were highly elevated in the WT mice as the result of the TAA treatment and consistent with the liver damage. We conclude that elevated TAA metabolites and reactive oxygen species that are produced by CYP-mediated drug metabolism trigger lipogenesis as well as liver damage via ER stress and determine the fate of the mice.

Double Knockout of Peroxiredoxin 4 (Prdx4) and Superoxide Dismutase 1 (Sod1) in Mice Results in Severe Liver Failure

“…We next performed Oil Red O staining of liver sections in these mice to characterize the intracytoplasmic vacuolar structures ( Figure 3(a) ). The results clearly showed the accumulation of larger numbers of lipid droplets in Sod1 −/− mouse livers than in WT mouse livers, consistent with previous reports [ 8 , 9 , 28 ], while no difference was found between Prdx4 −/y mouse livers and WT mouse livers. In the case of the DKO mouse livers, the numbers of lipid droplets were enhanced considerably compared to Sod1 −/− mouse livers.…”

Action of Melatonin on Severe Acute Liver Failure in Rats

“…This experimental model mimics the physiopathogenic and pathophysiological aspects of the disease in humans and helps in the understanding of its progress and the possibility of therapeutic intervention [16,[27][28][29].…”

The p53/p21/p16 and PI3K/Akt signaling pathways are involved in the ameliorative effects of maltol on D‐galactose‐induced liver and kidney aging and injury

“…Consistent with these findings, we found that maltol treatment significantly increased SOD and CAT levels in D‐Gal‐induced accelerated senescence and significantly reduced MDA levels. The cytochrome P450 enzyme system, mainly CYP2E1, is involved in the metabolism of endogenous and exogenous substances (Shirato, Homma, Lee, Kurahashi, & Fujii, 2017; Ye et al, 2012). Even though there was no additional increase in the CYP2E1 levels in aged WT mice, the increased levels of oxidative stress in WT mice could have been produced through CYP2E1‐mediated metabolism of endogenous substrates throughout the life span (Abdelmegeed, Choi, Ha, & Song, 2017).…”