Role of CYP2E1 in thioacetamide-induced mouse hepatotoxicity

Kang, Jin Seok; Wanibuchi, Hideki; Morimura, Keiichirou; Wongpoomchai, Rawiwan; Chusiri, Yaowares; Gonzalez, Frank J.; Fukushima, Shoji

doi:10.1016/j.taap.2007.11.010

Cited by 107 publications

(91 citation statements)

References 22 publications

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“…A similar phenomenon had been found in a previous study, in which the influence of octachlorostyrene treatment on inducing UGT mRNA levels was much more prominent than that on the glucuronidation activity toward 1-naphthol (Yanagiba et al, 2009). It is now well known that TAA is bioactivated mainly by CYP2E1 to produce reactive intermediates and the metabolite di-S-oxide, which is highly reactive against macromolecules by covalent binding and/or oxidative modifications (Kang et al, 2008). We hypothesized that the enzyme activity of UGTs may be inactivated by the reactive metabolites and/or reactive oxygen species generated from the process of TAA bioactivation.…”

Section: Discussionsupporting

confidence: 86%

Thioacetamide Intoxication Triggers Transcriptional Up-Regulation but Enzyme Inactivation of UDP-Glucuronosyltransferases

Hao¹,

Zhang²,

Jiang³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Thioacetamide (TAA) is a potent hepatotoxicant and has been widely used to develop experimental liver fibrosis/cirrhosis models. Although the liver toxicity of TAA has been extensively studied, little is known about its potential influence on UDP-glucuronosyltransferases (UGTs) associated with the development of liver fibrosis. The study presented here aimed to uncover the regulation patterns of UGTs in TAA-induced liver fibrosis of rats. Potential counteracting effects of hepatoprotective agents were also determined. TAA treatment for 8 weeks induced a significant transcriptional up-regulation of the major UGT isoforms, including UGT1A1, UGT1A6, and UGT2B1, accompanied with the dramatic elevations of most typical serum biomarkers of liver function and fibrosis scores. Upon TAA intoxication, the mRNA and protein levels of the major UGT isoforms were increased to 1.5-to 2.5-fold and 2.5-to 3.3-fold of that of the normal control, respectively. The hepatoprotective agents Schisandra spp. lignans extract and dimethyl diphenyl bicarboxylate could largely abolish TAA-induced up-regulation of all three UGT isoforms. However, enzyme activities of UGTs remained unchanged after TAA treatment. The dissociation of protein expression and enzyme activity could possibly be attributed to the inactivating effects of TAA, upon a NADPH-dependent bioactivation, on UGTs. This study suggests that the transcriptional up-regulation of UGTs may be an alternative mechanism of their preserved activities in liver fibrosis/cirrhosis.

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Section: Discussionsupporting

confidence: 86%

Thioacetamide Intoxication Triggers Transcriptional Up-Regulation but Enzyme Inactivation of UDP-Glucuronosyltransferases

Hao¹,

Zhang²,

Jiang³

et al. 2011

Drug Metab Dispos

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“…We were surprised to find that the enzyme activities of most P450s were not restored in proportion to the protein levels by treatment of hepatoprotective agents. In view that TAA can be bioactivated by CYP2E1 to produce highly reactive metabolite di-S-oxide (Kang et al, 2008), we hypothesized that TAA upon bioactivation may inactivate P450s. Our results showed that TAA exhibited both time-and concentration-dependent inhibitory effect on all the four P450 isozymes when NADPH was added to initiate bioactivations.…”

Section: Discussionmentioning

confidence: 99%

Cytochrome P450 Dysregulations in Thioacetamide-Induced Liver Cirrhosis in Rats and the Counteracting Effects of Hepatoprotective Agents

Xie¹,

Wang²,

Wang³

et al. 2012

Drug Metab Dispos

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ABSTRACT:Dysregulations of cytochromes P450 (P450s) under liver injury have been extensively studied. However, little is known about the possible reversing effects of hepatoprotective agents, the understanding of which is of great importance in guiding clinical dosage adjustment for patients with liver injury. This study aims to investigate the dysregulation patterns of major P450s in thioacetamide (TAA)-induced liver cirrhosis in rats and the potential counteracting effects of hepatoprotective agents schisandra lignans extract (SLE) and dimethyl diphenyl bicarboxylate (DDB). TAA intoxications for 6 weeks induced apparent liver injury and dramatically reduced the hepatic protein expressions of CYP1A2, CYP2C6, CYP2E1, and CYP3A2 to 18, 71, 30, and 21% of that in the normal control, respectively. Both SLE and DDB treatments could significantly reverse the TAA-induced loss of P450 protein levels, which may be ascribed to their hepatoprotective effects and direct P450-inducing effects that have been confirmed in healthy rats. However, the recovery of enzyme activities of most P450s by SLE and DDB treatment was less evident than that for the protein expression levels. TAA exhibited NADPH-, time-, and concentration-dependent inactivating effects on all of the four major P450 isozymes; both DDB and GSH showed little effects on counteracting such an inactivation efficacy. These findings provided a good explanation on the disproportional effects of hepatoprotective agents in recovering the protein levels and enzyme activities of TAA-induced dysregulated P450s.

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“…20 The oxidation of TAA appears to be mediated primarily through CYP2E1, although under varying physiological conditions, the FAD-containing monooxygenases may play a more important role. 20,22,23 When Cyp2e1-null mice were acutely exposed to TAA, they were protected from liver injury, elevation in markers of inflammation, and oxidative stress. By contrast, wild-type mice showed markedly increased mRNA levels of tumour necrosis factor (TNF)-a, interleukin (IL)-6 and glutathione peroxidase plus developed centrilobular necrosis and inflammation.…”

Section: Mechanisms and Pattern Of Liver Injurymentioning

confidence: 99%

Standard Operating Procedures in Experimental Liver Research: Thioacetamide model in mice and rats

et al. 2015

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In addition to carbon tetrachloride (CCl 4 ), thioacetamide (TAA) represents a second widely used model for the induction of experimental liver fibrosis, but can also be employed for the development of acute liver failure and liver tumours. While TAA itself is not hepatotoxic, its reactive metabolites covalently bind to proteins and lipids thereby causing oxidative stress and centrilobular necrosis. Compared with CCl 4 , TAA leads to more periportal infiltrates and more pronounced ductal proliferation. While TAA has been shown to induce liver fibrosis development in several different mouse strains, wide variations in the administration routes, doses and treatment durations have been reported. Therefore, an adoption of a universal standard operating procedure for the administration of TAA is urgently needed. For that purpose, we are presenting here two TAA models (intraperitoneal administration of 150 mg/kg of TAA three times per week for 11 weeks in rats, and TAA administration in drinking water at 300 mg/L for 2-4 months in mice) with which we have had success in reliably and reproducibly developing chronic liver injury and fibrosis.

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Role of CYP2E1 in thioacetamide-induced mouse hepatotoxicity

Cited by 107 publications

References 22 publications

Thioacetamide Intoxication Triggers Transcriptional Up-Regulation but Enzyme Inactivation of UDP-Glucuronosyltransferases

Thioacetamide Intoxication Triggers Transcriptional Up-Regulation but Enzyme Inactivation of UDP-Glucuronosyltransferases

Cytochrome P450 Dysregulations in Thioacetamide-Induced Liver Cirrhosis in Rats and the Counteracting Effects of Hepatoprotective Agents

Standard Operating Procedures in Experimental Liver Research: Thioacetamide model in mice and rats

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