Sensitivity of Liver Injury in Heterozygous <i>Sod2</i> Knockout Mice Treated with Troglitazone or Acetaminophen

Fujimoto, Kazunori; Kumagai, Kazuyoshi; Ito, Kazumi; Arakawa, Shingo; Ando, Yumiko; Oda, Sen-ichi; Yamoto, Takashi; Manabe, Sunao

doi:10.1177/0192623308329282

Cited by 96 publications

(65 citation statements)

References 18 publications

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“…Ong and coworkers 19 reported that Sod2 þ/À knockout mice developed increased serum alanine aminotransferase activity and hepatic necrosis after prolonged troglitazone administration. However, Fujimoto and coworkers 20 were unable to reproduce these results. Furthermore, although enhanced SOD2 activity and subsequently increased H 2 O 2 levels can be beneficial for preventing cell proliferation and thus may be useful in cancer treatment, 21 they can also enhance lipid peroxidation, causing mitochondrial injury.…”

Section: Discussionmentioning

confidence: 95%

Mitochondrial superoxide dismutase and glutathione peroxidase in idiosyncratic drug-induced liver injury

et al. 2010

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Drug-induced liver injury (DILI) susceptibility has a potential genetic basis. We have evaluated possible associations between the risk of developing DILI and common genetic variants of the manganese superoxide dismutase (SOD2 Val16Ala) and glutathione peroxidase (GPX1 Pro200Leu) genes, which are involved in mitochondrial oxidative stress management. Genomic DNA from 185 DILI patients assessed by the Council for International Organizations of Medical Science scale and 270 sex-and age-matched controls were analyzed. The SOD2 and GPX1 genotyping was performed using polymerase chain reaction restriction fragment length polymorphism and TaqMan probed quantitative polymerase chain reaction, respectively. The statistical power to detect the effect of variant alleles with the observed odds ratio (OR) was 98.2% and 99.7% for bilateral association of SOD2 and GPX1, respectively. The SOD2 Ala/Ala genotype was associated with cholestatic/mixed damage (OR 5 2.3; 95% confidence interval [CI] 5 1.4-3.8; corrected P [Pc] 5 0.0058), whereas the GPX1 Leu/Leu genotype was associated with cholestatic injury (OR 5 5.1; 95%CI 5 1.6-16.0; Pc 5 0.0112). The presence of two or more combined risk alleles (SOD2 Ala and GPX1 Leu) was more frequent in DILI patients (OR 5 2.1; 95%CI 5 1.4-3.0; Pc 5 0.0006). Patients with cholestatic/mixed injury induced by mitochondria hazardous drugs were more prone to have the SOD2 Ala/Ala genotype (OR 5 3.6; 95%CI 5 1.4-9.3; Pc 5 0.02). This genotype was also more frequent in cholestatic/mixed DILI induced by pharmaceuticals producing quinone-like or epoxide metabolites (OR 5 3.0; 95%CI 5 1.7-5.5; Pc 5 0.0008) and S-oxides, diazines, nitroanion radicals, or iminium ions (OR 5 16.0; 95%CI 5 1.8-146.1; Pc 5 0.009). Conclusion: Patients homozygous for the SOD2 Ala allele and the GPX1 Leu allele are at higher risk of developing cholestatic DILI. SOD2 Ala homozygotes may be more prone to suffer DILI from drugs that are mitochondria hazardous or produce reactive intermediates. (HEPATOLOGY 2010;52:303-312)

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Section: Discussionmentioning

confidence: 95%

Mitochondrial superoxide dismutase and glutathione peroxidase in idiosyncratic drug-induced liver injury

et al. 2010

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“…MnSOD thus limits the reaction of superoxide with nitric oxide to form the reactive nitrogen species peroxynitrite. Because the hepatotoxicity of APAP occurs with increased nitration of proteins and mitochondrial dysfunction, and MnSOD heterozygote mice have been reported to be more sensitive to APAP toxicity compared with wild-type mice (Fujimoto et al, 2009), we examined hepatic MnSOD activity and possible nitration in APAPinduced hepatotoxicity.…”

Section: Introductionmentioning

confidence: 99%

Acetaminophen-Induced Hepatotoxicity in Mice Occurs with Inhibition of Activity and Nitration of Mitochondrial Manganese Superoxide Dismutase

Agarwal¹,

MacMillan-Crow²,

Rafferty³

et al. 2010

J Pharmacol Exp Ther

104

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In overdose the analgesic/antipyretic acetaminophen (APAP) is hepatotoxic. Toxicity is mediated by initial hepatic metabolism to N-acetyl-p-benzoquinone imine (NAPQI). After low doses NAPQI is efficiently detoxified by GSH. However, in overdose GSH is depleted, NAPQI covalently binds to proteins as APAP adducts, and oxygen/nitrogen stress occurs. Toxicity is believed to occur by mitochondrial dysfunction. Manganese superoxide dismutase (MnSOD) inactivation by protein nitration has been reported to occur during other oxidant stress-mediated diseases. MnSOD is a critical mitochondrial antioxidant enzyme that prevents peroxynitrite formation within the mitochondria. To examine the role of MnSOD in APAP toxicity, mice were treated with 300 mg/kg APAP. GSH was significantly reduced by 65% at 0.5 h and remained reduced from 1 to 4 h. Serum alanine aminotransferase did not significantly increase until 4 h and was 2290 IU/liter at 6 h. MnSOD activity was significantly reduced by 50% at 1 and 2 h. At 1 h, GSH was significantly depleted by 62 and 80% at nontoxic doses of 50 and 100 mg/kg, respectively. No further GSH depletion occurred with hepatotoxic doses of 200 and 300 mg/kg APAP. A dose response decrease in MnSOD activity was observed for APAP at 100, 200, and 300 mg/kg. Immunoprecipitation of MnSOD from livers of APAP-treated mice followed by Western blot analysis revealed nitrated MnSOD. APAP-MnSOD adducts were not detected. Treatment of recombinant MnSOD with NAPQI did not produce APAP protein adducts. The data indicate that MnSOD inactivation by nitration is an early event in APAP-induced hepatic toxicity.

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“…Because of safety concerns over its use, troglitazone was withdrawn from the U.S. market in 2000. On the other hand, in preclinical species, it is very difficult to reproduce the troglitazone-induced liver injury, even when using a dose of troglitazone greater than the clinical dose (Watanabe et al, 2000;Fujimoto et al, 2009). This has hindered the clarification of the exact mechanisms of troglitazoneinduced hepatotoxicity.…”

Section: Introductionmentioning

confidence: 99%

Involvement of Different Human Glutathione Transferase Isoforms in the Glutathione Conjugation of Reactive Metabolites of Troglitazone

Okada

Maeda²,

Nishiyama³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Null mutation of glutathione transferase (GST) M1 and GSTT1 was reported to correlate statistically with an abnormal increase in the plasma levels of alanine aminotransferase or aspartate aminotransferase caused by troglitazone in diabetic patients (Clin Pharmacol Ther, 73:435-455, 2003). This clinical evidence leads to the hypothesis that GSH conjugation catalyzed by GSTT1 and GSTM1 has a role in the elimination of reactive metabolites of troglitazone. However, the contribution of GST isoforms expressed in human liver to the detoxification of reactive metabolites of troglitazone has not yet been clarified. We investigated the involvement of human GST isoforms in the GSH conjugation of reactive metabolites of troglitazone using recombinant GST enzymes. Five reported GSH conjugates of reactive metabolites were produced from troglitazone after incubation with liver microsomes, NADPH, and GSH in a GSH concentration-dependent manner. Addition of human recombinant GSTA1, GSTA2, GSTM1, or GSTP1 protein to the incubation mixture further increased the GSH conjugates. However, the addition of GSTT1 did not show any catalytic effect. It is of interest that one of the reactive metabolites with a quinone structure was predominantly conjugated with GSH by GSTM1. Thus, we demonstrated that the GST isoforms contributed differently to the GSH conjugation of individual reactive metabolites of troglitazone, and GSTM1 is the most important GST isoform in the GSH conjugation of a specific reactive metabolite produced from the cytotoxic, quinone-form metabolite of troglitazone.

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Sensitivity of Liver Injury in Heterozygous Sod2 Knockout Mice Treated with Troglitazone or Acetaminophen

Cited by 96 publications

References 18 publications

Mitochondrial superoxide dismutase and glutathione peroxidase in idiosyncratic drug-induced liver injury

Mitochondrial superoxide dismutase and glutathione peroxidase in idiosyncratic drug-induced liver injury

Acetaminophen-Induced Hepatotoxicity in Mice Occurs with Inhibition of Activity and Nitration of Mitochondrial Manganese Superoxide Dismutase

Involvement of Different Human Glutathione Transferase Isoforms in the Glutathione Conjugation of Reactive Metabolites of Troglitazone

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