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.
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Abbreviations
- NAFLD:
-
Non-alcoholic fatty liver disease
- TAA:
-
Thioacetamide
- TAA-SO:
-
Thioacetamide S-oxide
- TAA-SO2 :
-
Thioacetamide S,S-dioxide
- SOD:
-
Superoxide dismutase
- ROS:
-
Reactive oxygen species
- Prx:
-
Peroxiredoxin
- ALT:
-
Alanine aminotransferase
- ER:
-
Endoplasmic reticulum
- CYP:
-
Cytochrome P450
- KO:
-
Knockout
- WT:
-
Wild type
- i.p.:
-
Intraperitoneally
- PBS:
-
Phosphate-buffered saline
- ATTM:
-
Ammonium tetrathiomolybdate
- H&E:
-
Hematoxylin and eosin
- TG:
-
Triglyceride
- Nrf2:
-
NF-E2-related factor 2
- HNE:
-
4-Hydroxyl 2-nonenal
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J.L. is a scholarship recipient from the Otsuka Toshimi Scholarship Foundation.
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Shirato, T., Homma, T., Lee, J. et al. Oxidative stress caused by a SOD1 deficiency ameliorates thioacetamide-triggered cell death via CYP2E1 inhibition but stimulates liver steatosis. Arch Toxicol 91, 1319–1333 (2017). https://doi.org/10.1007/s00204-016-1785-9
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DOI: https://doi.org/10.1007/s00204-016-1785-9