Benzyl alcohol protects against acetaminophen hepatotoxicity by inhibiting cytochrome P450 enzymes but causes mitochondrial dysfunction and cell death at higher doses. (December 2015)

• Record Type: Journal Article
• Authors: Du, Kuo; McGill, Mitchell R.; Xie, Yuchao; Jaeschke, Hartmut
• Is Part Of: Food and chemical toxicology. Volume 86(2015)
• Page Start: 253
• Page End: 261
• Publication Date: 2015-12
• Subjects: Acetaminophen hepatotoxicity -- Benzyl alcohol -- Acute liver failure -- Mitochondria -- Sterile inflammation -- Human hepatocytes; AIF apoptosis-inducing factor -- ALT alanine aminotransferase -- APAP acetaminophen -- BA benzyl alcohol -- CYP cytochrome P450 -- DAMPs damage associated molecular patterns -- 7-EFC 7-ethoxy-4-trifluoromethylcoumarin -- GSH glutathione -- GSSG glutathione disulfide -- HPLC-ECD high-pressure liquid chromatography with electrochemical detection -- LDH lactate dehydrogenase -- MPT mitochondrial permeability transition -- NAC N-acetylcysteine -- NAPQI N-acetyl-p-benzoquinone imine -- PHH primary human hepatocytes -- ROS reactive oxygen species -- Smac second mitochondria-derived activator of caspases -- TLR toll like receptor; Toxicology -- Periodicals; Food poisoning -- Periodicals; Food Poisoning -- Periodicals; Toxicology -- Periodicals; Toxicologie -- Périodiques; Intoxications alimentaires -- Périodiques; Food poisoning; Toxicology; Periodicals; Electronic journals; 615.9
• DOI: 10.1016/j.fct.2015.10.016
• Languages: English
• ISSNs: 0278-6915

Abstract

Abstract: Acetaminophen (APAP) hepatotoxicity is a serious public health problem in western countries. Current treatment options for APAP poisoning are limited and novel therapeutic intervention strategies are needed. A recent publication suggested that benzyl alcohol (BA) protects against APAP hepatotoxicity and could serve as a promising antidote for APAP poisoning. To assess the protective mechanisms of BA, C56Bl/6J mice were treated with 400 mg/kg APAP and/or 270 mg/kg BA. APAP alone caused extensive liver injury at 6 h and 24 h post-APAP. This injury was attenuated by BA co-treatment. Assessment of protein adduct formation demonstrated that BA inhibits APAP metabolic activation. In support of this, in vitro experiments also showed that BA dose-dependently inhibits cytochrome P450 activities. Correlating with the hepatoprotection of BA, APAP-induced oxidant stress and mitochondrial dysfunction were reduced. Similar results were obtained in primary mouse hepatocytes. Interestingly, BA alone caused mitochondrial membrane potential loss and cell toxicity at high doses, and its protective effect could not be reproduced in primary human hepatocytes (PHH). We conclude that BA protects against APAP hepatotoxicity mainly by inhibiting cytochrome P450 enzymes in mice. Considering its toxic effect and the loss of protection in PHH, BA is not a clinically useful treatment option for APAP overdose patient. Highlights: Benzyl alcohol protects against APAP hepatotoxicity in mice and mouse hepatocytes. BA protects by inhibiting metabolic activation of APAP rather than inflammation. BA is toxic and does not protect against APAP-induced cell death in human hepatocytes. BA is not likely a realistic therapeutic option for treatment of APAP overdose.