Trifluoperazine inhibits acetaminophen-induced hepatotoxicity and hepatic reactive nitrogen formation in mice and in freshly isolated hepatocytes

Toxicology Reports
Sudip BanerjeeJack A Hinson

Abstract

The hepatotoxicity of acetaminophen (APAP) occurs by initial metabolism to N-acetyl-p-benzoquinone imine which depletes GSH and forms APAP-protein adducts. Subsequently, the reactive nitrogen species peroxynitrite is formed from nitric oxide (NO) and superoxide leading to 3-nitrotyrosine in proteins. Toxicity occurs with inhibited mitochondrial function. We previously reported that in hepatocytes the nNOS (NOS1) inhibitor NANT inhibited APAP toxicity, reactive nitrogen and oxygen species formation, and mitochondrial dysfunction. In this work we examined the effect of trifluoperazine (TFP), a calmodulin antagonist that inhibits calcium induced nNOS activation, on APAP hepatotoxicity and reactive nitrogen formation in murine hepatocytes and in vivo. In freshly isolated hepatocytes TFP inhibited APAP induced toxicity, reactive nitrogen formation (NO, GSNO, and 3-nitrotyrosine in protein), reactive oxygen formation (superoxide), loss of mitochondrial membrane potential, decreased ATP production, decreased oxygen consumption rate, and increased NADH accumulation. TFP did not alter APAP induced GSH depletion in the hepatocytes or the formation of APAP protein adducts which indicated that reactive metabolite formation was not inhibite...Continue Reading

References

Nov 20, 2003·The Journal of Biological Chemistry·Alexei P KudinWolfram S Kunz
Mar 6, 2008·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·William M LeeJay H Hoofnagle
Feb 15, 2011·Toxicology and Applied Pharmacology·Shubhra ChaudhuriLaura P James

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Citations

Apr 2, 2019·Biochemistry and Cell Biology = Biochimie Et Biologie Cellulaire·Marwa G A HegazyNesma M Helal
Nov 10, 2020·Epigenetics : Official Journal of the DNA Methylation Society·Laurie K SvobodaDana C Dolinoy
Dec 22, 2020·Experimental Biology and Medicine·Xue-Liang DangAi-Dong Wen
Oct 27, 2020·Drug Metabolism Reviews·Mitchell R McGill, Jack A Hinson

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Methods Mentioned

BETA
Assay
protein assay

Software Mentioned

Prism GraphPad
Seahorse XF - 96

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