Human Hepatic Mitochondria Generate Reactive Oxygen Species and Undergo the Permeability Transition in Response to Hydrophobic Bile Acids

Sokol, Ronald J.; Dahl, Rolf; Devereaux, Michael W.; Yerushalmi, Baruch; Kobak, Gregory E.; Gumpricht, Eric

doi:10.1097/01.mpg.0000170600.80640.88

Cited by 95 publications

(72 citation statements)

References 45 publications

(117 reference statements)

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“…Indeed, retention of hydrophobic bile acids is known to enhance mitochondrial oxidative stress. 26 The fact that cholestatic patients are generally older than hepatocellular patients supports a role for SOD2 in cholestatic injury, as the antioxidant defence system is known to decline with age. 8,27 In line with this theory was the finding that our cholestatic/mixed DILI cases homozygous for the SOD2 Ala allele had a Fig.…”

Section: Discussionmentioning

confidence: 99%

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: 99%

Mitochondrial Superoxide Dismutase and Glutathione Peroxidase in Idiosyncratic Drug-Induced Liver Injury

et al. 2010

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“…Bile acids have also been postulated to cause direct mitochondrial cytotoxicity thereby activating the intrinsic pathway of apoptosis (12,31). Indeed, bile acids induced mitochondrial generation of reactive oxygen species, mitochondrial membrane potential depolarization, and the mitochondrial permeability transition in primary rat hepatocytes (32).…”

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

“…GCDCA can dose-dependently induce the mitochondrial permeability transition in isolated human mitochondria (12). In addition, a marked increase in reactive oxygen species production was observed within minutes in the mitochondria treated with GCDCA (12). Procaspase-8 appears to be processed late in Fas-dependent hepatocyte apoptosis, suggesting that only a small amount of procaspase-8 may actually be activated at the Fas receptor (13).…”

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Bile Acid-induced Apoptosis in Hepatocytes Is Caspase-6-dependent

Rust

Wild

Bernt

et al. 2009

Journal of Biological Chemistry

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Apoptosis induced by hydrophobic bile acids is thought to contribute to liver injury during cholestasis. Caspase-6 is an executioner caspase that also appears to have regulatory functions in hematopoetic cell lines. We aimed to elucidate the role of caspase-6 in bile acid-induced apoptosis. The major human hydrophobic bile acid, glycochenodeoxycholic acid (GCDCA, 75 mol/liter), rapidly induced caspase-6 cleavage in HepG2-Ntcp human hepatoma cells. GCDCA-induced, but not tumor necrosis factor ␣-or etoposide-induced activation of effector caspases-3 and -7 was significantly reduced by 50% in caspase-6-deficient HepG2-Ntcp cells as well as in primary rat hepatocytes pretreated with a caspase-6 inhibitor. Inhibition of caspase-9 reduced GCDCA-induced activation of caspase-6, whereas inhibition of caspase-6 reduced activation of caspase-8 placing caspase-6 between caspase-9 and caspase-8. GCDCA also induced apoptosis in Fas-deficient Hep3B-Ntcp and HuH7-Ntcp hepatoma cells. In addition, GCDCA-induced apoptosis was reduced by 50% in FADD-deficient HepG2-Ntcp cells, whereas apoptosis induced by tumor necrosis factor ␣ was reduced by 90%. Collectively, these observations suggest that GCDCA can induce hepatocyte apoptosis in the absence of death receptor signaling, presumably by a compensatory mitochondrial pathway. In conclusion, caspase-6 appears to play an important regulatory role in the promotion of bile acid-induced apoptosis as part of a feedback loop.Cholestasis is a feature of many chronic human liver diseases like primary biliary cirrhosis (1). Hepatocyte damage by toxic bile acids is assumed to represent a key event for progression of cholestatic liver diseases (2). Toxic bile acids induce hepatocellular apoptosis, thereby providing a cellular mechanism for bile acid-mediated liver injury and fibrogenesis (3-6). The glycine and taurine conjugates of chenodeoxycholic acid (GCDCA, TCDCA) 2 are the predominant dihydroxy bile acids in cholestatic patients and have been held responsible for cholestasisassociated liver injury (7). GCDCA is thought to induce hepatocyte apoptosis by Fas death receptor-dependent signaling that is independent of Fas ligand (8). In a recently proposed model, activation of NADPH oxidase isoforms by GCDCA is followed by generation of reactive oxygen species, which results in epidermal growth factor receptor-dependent tyrosine phosphorylation of Fas (5, 9). GCDCA-induced oligomerization of Fas then causes activation of the initiator caspase-8, which requires the adaptor protein FADD. In hepatocytes, caspase-8 then would cause apoptosis via the mitochondrial pathway (10).In cell-free systems, however, toxic bile acids like GCDCA can directly cause mitochondrial damage leading to cytochrome c leakage, which is followed by the activation of caspase-9 via the apoptosome (11). GCDCA can dose-dependently induce the mitochondrial permeability transition in isolated human mitochondria (12). In addition, a marked increase in reactive oxygen species production was observed within minutes in the m...

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“…Decreased serum bile acids have been related to the accumulation of toxic and even carcinogenic bile acid in liver that may be caused by the alteration in the bile acid transport pathway [50]. GCDCA has been reported as an inducer of apoptosis in human hepatocyte [51]. Abnormality of bile acid biosynthesis leads to development and progression of liver cancer [52].…”

Section: Liver Cirrhosis and Chronic Liver Diseasesmentioning

confidence: 99%

UPLC-based metabonomic applications for discovering biomarkers of diseases in clinical chemistry

Zhao

Cheng

Vaziri

et al. 2014

Clinical Biochemistry

120

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a b s t r a c t a r t i c l e i n f oObjectives: Metabonomics is a powerful and promising analytic tool that allows assessment of global lowmolecular-weight metabolites in biological systems. It has a great potential for identifying useful biomarkers for early diagnosis, prognosis and assessment of therapeutic interventions in clinical practice. The aim of this review is to provide a brief summary of the recent advances in UPLC-based metabonomic approach for biomarker discovery in a variety of diseases, and to discuss their significance in clinical chemistry.Design and methods: All the available information on UPLC-based metabonomic applications for discovering biomarkers of diseases were collected via a library and electronic search (using Web of Science, Pubmed, ScienceDirect, Springer, Google Scholar, etc.).Results: Metabonomics has been used in clinical chemistry to identify and evaluate potential biomarkers and therapeutic targets in various diseases affecting the liver (hepatocarcinoma and liver cirrhosis), lung (lung cancer and pneumonia), gastrointestinal tract (colorectal cancer) and urogenital tract (prostate cancer, ovarian cancer and chronic kidney disease), as well as metabolic diseases (diabetes) and neuropsychiatric disorders (Alzheimer's disease and schizophrenia), etc.Conclusions: The information provided highlights the potential value of determination of endogenous lowmolecular-weight metabolites and the advantages and potential drawbacks of the application of UPLC-based metabonomics in clinical setting.

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Human Hepatic Mitochondria Generate Reactive Oxygen Species and Undergo the Permeability Transition in Response to Hydrophobic Bile Acids

Cited by 95 publications

References 45 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

Bile Acid-induced Apoptosis in Hepatocytes Is Caspase-6-dependent

UPLC-based metabonomic applications for discovering biomarkers of diseases in clinical chemistry

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