p53 attenuates acetaminophen-induced hepatotoxicity by regulating drug-metabolizing enzymes and transporter expression

Cell Death & Disease
Jiahong SunHuichang Bi

Abstract

Acetaminophen (APAP) overdose is the most frequent cause of drug-induced acute liver failure. Inhibition of APAP metabolic activation and promotion in APAP disposition are important to protect against APAP-induced liver injury. Tumor suppressor p53 is traditionally recognized as a surveillance molecule to preserve genome integrity. Recent studies have emerged on discovering its functions in metabolic regulation. Our previous study reported that p53 promoted bile acid disposition and alleviated cholestastic syndrome. Here, we examined the effect of doxorubicin (Dox)-mediated p53 activation on APAP-induced hepatotoxicity in mice and revealed a novel role of p53 in regulating APAP metabolism and disposition. Histopathological and biochemical assessments demonstrated that administration of Dox (10 mg/kg/d) before APAP treatment (400 mg/kg) significantly alleviated APAP-induced hepatotoxicity. Dox treatment prevented APAP-induced GSH depletion and lipid peroxidation. p53-null mice were more susceptible to APAP-induced liver injury. Further, we found that the expression of drug-metabolizing enzymes and transporters CYPs, SULTs and MRPs was regulated by p53. Dox treatment also promoted Nrf2 activation and increased the expression of N...Continue Reading

References

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Citations

Jul 28, 2019·Oxidative Medicine and Cellular Longevity·Yan-Yan MengQi-Zhu Tang
Dec 24, 2019·Acta Pharmaceutica Sinica. B·Yuhua LiHuichang Bi
Jan 24, 2021·Cellular and Molecular Gastroenterology and Hepatology·Laura Elisa Buitrago-MolinaArndt Vogel
Mar 5, 2021·Phytomedicine : International Journal of Phytotherapy and Phytopharmacology·Ying-Yuan ZhaoHui-Chang Bi
Apr 1, 2021·Seminars in Cancer Biology·Yanqing Liu, Wei Gu
Apr 4, 2021·International Journal of Molecular Sciences·Samara NaimThomas Kaufmann
Apr 6, 2021·Frontiers in Cell and Developmental Biology·Wenhui DongYong Xu
Jul 3, 2021·Toxicology and Applied Pharmacology·Mariana SemeniukMaría Laura Ruiz
Jul 8, 2021·Antioxidants & Redox Signaling·Anup Ramachandran, Hartmut Jaeschke
Aug 2, 2020·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Apu ChowdhurySicen Wang

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Methods Mentioned

BETA
MDA
confocal microscopy
transfection
Protein Assay

Software Mentioned

GraphPad Prism

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