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2,3,4',5-tetrahydroxystilbene-2-O-?-D-glucoside exacerbates acetaminophen-induced hepatotoxicity by inducing hepatic expression of CYP2E1, CYP3A4 and CYP1A2.

ABSTRACT: Hepatotoxicity induced by medicinal herb Polygonum multiflorum Thunb. attracts wide attention in the world recently. 2,3,4',5-tetrahydroxystilbene-2-O-?-D-glucoside (TSG) is a main active compound in Polygonum multiflorum Thunb. This study aims to observe TSG-provided the aggravation on acetaminophen (APAP)-induced hepatotoxicity in mice by inducing hepatic expression of cytochrome P450 (CYP450) enzymes. Serum alanine/aspartate aminotransferase (ALT/AST) analysis and liver histological evaluation showed that TSG (200, 400, 800?mg/kg) exacerbated the hepatotoxicity induced by sub-toxic dose of APAP (200?mg/kg) in mice, but TSG alone had no hepatotoxicity. TSG aggravated hepatic reduced glutathione (GSH) depletion and APAP-cysteine adducts (APAP-CYS) formation induced by APAP in mice. TSG increased the expression of CYP2E1, CYP3A4 and CYP1A2 both in mice and in human normal liver L-02 hepatocytes. TSG also enhanced liver catalytic activity of CYP2E1, CYP3A4 and CYP1A2 in mice. TSG induced the nuclear translocation of aryl hydrocarbon receptor (AHR) and pregnane X receptor (PXR), and TSG-provided the aggravation on APAP-induced hepatotoxicity in mice was reversed by PXR or AHR inhibitors. In summary, our results demonstrate that TSG enhances hepatic expression of CYP3A4, CYP2E1 and CYP1A2, and thus exacerbates the hepatotoxicity induced by APAP in mice. PXR and AHR both play some important roles in this process.

SUBMITTER: Xu S

PROVIDER: S-EPMC5705655 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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2,3,4',5-tetrahydroxystilbene-2-O-β-D-glucoside exacerbates acetaminophen-induced hepatotoxicity by inducing hepatic expression of CYP2E1, CYP3A4 and CYP1A2.

Xu Shangfu S Liu Jie J Shi Jingshan J Wang Zhengtao Z Ji Lili L

Scientific reports 20171128 1

Hepatotoxicity induced by medicinal herb Polygonum multiflorum Thunb. attracts wide attention in the world recently. 2,3,4',5-tetrahydroxystilbene-2-O-β-D-glucoside (TSG) is a main active compound in Polygonum multiflorum Thunb. This study aims to observe TSG-provided the aggravation on acetaminophen (APAP)-induced hepatotoxicity in mice by inducing hepatic expression of cytochrome P450 (CYP450) enzymes. Serum alanine/aspartate aminotransferase (ALT/AST) analysis and liver histological evaluatio ...[more]

PMID: 29184146

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Project description:Acetaminophen (APAP) is one of the most popular and safe pain medications worldwide. However, due to its wide availability, it is frequently implicated in intentional or unintentional overdoses where it can cause severe liver injury and even acute liver failure (ALF). In fact, APAP toxicity is responsible for 46% of all ALF cases in the United States. Early mechanistic studies in mice demonstrated the formation of a reactive metabolite, which is responsible for hepatic glutathione depletion and initiation of the toxicity. This insight led to the rapid introduction of N-acetylcysteine as a clinical antidote. However, more recently, substantial progress was made in further elucidating the detailed mechanisms of APAP-induced cell death. Mitochondrial protein adducts trigger a mitochondrial oxidant stress, which requires amplification through a MAPK cascade that ultimately results in activation of c-jun N-terminal kinase (JNK) in the cytosol and translocation of phospho-JNK to the mitochondria. The enhanced oxidant stress is responsible for the membrane permeability transition pore opening and the membrane potential breakdown. The ensuing matrix swelling causes the release of intermembrane proteins such as endonuclease G, which translocate to the nucleus and induce DNA fragmentation. These pathophysiological signaling mechanisms can be additionally modulated by removing damaged mitochondria by autophagy and replacing them by mitochondrial biogenesis. Importantly, most of the mechanisms have been confirmed in human hepatocytes and indirectly through biomarkers in plasma of APAP overdose patients. The extensive necrosis caused by APAP overdose leads to a sterile inflammatory response. Although recruitment of inflammatory cells is necessary for removal of cell debris in preparation for regeneration, these cells have the potential to aggravate the injury. This review touches on the newest insight into the intracellular mechanisms of APAP-induced cells death and the resulting inflammatory response. Furthermore, it discusses the translation of these findings to humans and the emergence of new therapeutic interventions.

Dataset Information

2,3,4',5-tetrahydroxystilbene-2-O-?-D-glucoside exacerbates acetaminophen-induced hepatotoxicity by inducing hepatic expression of CYP2E1, CYP3A4 and CYP1A2.

Publications

2,3,4',5-tetrahydroxystilbene-2-O-β-D-glucoside exacerbates acetaminophen-induced hepatotoxicity by inducing hepatic expression of CYP2E1, CYP3A4 and CYP1A2.

Similar Datasets

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