The role of mitochondrial injury in bromobenzene and furosemide induced hepatotoxicity

Wong, Simon; Card, Jeffrey W.; Racz, William J.

doi:10.1016/s0378-4274(00)00218-6

Cited by 49 publications

(56 citation statements)

References 24 publications

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“…Unlike APAP, FS hepatotoxicity did not accompany changes in hepatic GSH levels as previously observed. 20,21) Interestingly, only NAC and GSH, both of which could protect mice against APAP hepatotoxicity via GSH-independent mechanisms as described above, attenuated FS hepatotoxicity. Thus, the FS model supports the idea that a protective mechanism of NAC and GSH involves factors other than GSH replenishment, such as cytokine modulation.…”

Section: Discussionmentioning

confidence: 87%

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Protective Effects of Exogenous Glutathione and Related Thiol Compounds against Drug-Induced Liver Injury

Masubuchi

Nakayama

Sadakata

2011

Biological & Pharmaceutical Bulletin

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Acetaminophen (APAP), a commonly used analgesic, is usually safe when administered at therapeutic doses. However, APAP overdose causes liver injury both in experimental animals and humans. APAP has been used extensively to develop an animal model of drug-induced liver injury. The toxicity is initiated by cytochrome P450 (CYP) metabolism into N-acetyl-p-benzoquinone imine (NAPQI), and the high reactivity of NAPQI with sulfhydryl groups results in depletion of reduced glutathione (GSH) in hepatocytes, followed by covalent binding to intracellular proteins.1-3) Therefore, hepatic GSH levels are important in protecting against APAP hepatotoxicity, and enhancement of hepatic GSH is a reasonable strategy for the treatment of APAP intoxication.N-Acetylcysteine (NAC) is clinically used as an antidote for APAP intoxication.4) It is thought that NAC provides cysteine (CYS) as a precursor of GSH which traps NAPQI, leading to a decrease in toxicity (Fig. 1). 5) However, NAC was shown to improve patient outcome after late administration 6) ; this could not be explained by trapping NAPQI. In fact, treatment of mice with NAC after APAP administration protected against hepatic necrosis without reducing covalent binding, suggesting that mechanisms other than GSH replenishment are involved in the hepatoprotective effects of NAC. [7][8][9] In contrast to NAC, GSH itself is not used as an antidote for APAP intoxication. It is believed that intraperitoneal administration of GSH is less effective in restoring hepatic GSH, probably because exogenous GSH can not be taken up by hepatocytes, whereas ethyl esters of GSH are proposed as GSH precursors that are taken up and hydrolyzed by hepatocytes into GSH (Fig. 1). 10) On the other hand, intravenously administered GSH was found to protect against APAP hepatotoxicity.11) It is considered that intravenous GSH rapidly degrades in the kidney, is absorbed as amino acids, and is used to synthesize GSH in the liver, which could led to hepatoprotection. These studies suggest the potential importance of restoring hepatic GSH levels in the protection against APAP hepatotoxicity by exogenous thiol compounds. The objective of this study was to clarify the role of GSH supplementation in the hepatoprotective action of NAC and other thiol compounds, which could lead to the development of a new hepatoprotective agent. We found that a relatively low dose of thiol compounds, GSH, NAC, CYS, and glutathione-monoethyl ester (GSH-EE), protected mice against APAP hepatotoxicity together with different abilities to re- An overdose of acetaminophen (APAP) causes liver injury both in experimental animals and humans. NAcetylcysteine (NAC) is clinically used as an antidote for APAP intoxication, and it is thought to act by providing cysteine as a precursor of glutathione, which traps a reactive metabolite of APAP. Other hepatoprotective mechanisms of NAC have also been suggested. Here, we examined the effects of thiol compounds with different abilities to restore hepatic glutathione, on hepatotoxicity of APAP and f...

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Section: Discussionmentioning

confidence: 87%

“…5B), which agrees with previous observations. 20,21) We examined the protective effects of thiol compounds on FS hepatotoxicity, which does not require hepatic 368 Vol. 34, No.…”

Section: )mentioning

confidence: 99%

Protective Effects of Exogenous Glutathione and Related Thiol Compounds against Drug-Induced Liver Injury

Masubuchi

Nakayama

Sadakata

2011

Biological & Pharmaceutical Bulletin

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“…This hypothesis was confirmed by demonstrating that liver cell damage caused by furosemide, a hepatotoxicant not believed to affect mitochondria (43), resulted in ALT release, but not a statistically significant increase in either mtDNA or GDH in mouse plasma. In contrast, APAP overdose triggers release of both ALT and large amounts of GDH and mtDNA into the plasma of mice.…”

Section: Figurementioning

confidence: 79%

“…Furosemide is a loop diuretic prescribed for cases of hypertension and congestive heart failure. At high doses, furosemide can cause liver injury without affecting mitochondrial function (43). Mice treated with this drug had a significant increase in ALT activity in serum at 24 hours ( Figure 5A), with centrilobular necrosis similar to APAP-induced injury ( Figure 6).…”

Section: Study Design and Patient Informationmentioning

confidence: 97%

The mechanism underlying acetaminophen-induced hepatotoxicity in humans and mice involves mitochondrial damage and nuclear DNA fragmentation

McGill

Sharpe²,

Williams³

et al. 2012

J. Clin. Invest.

647

586

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Acetaminophen (APAP) overdose is the predominant cause of acute liver failure in the United States. Toxicity begins with a reactive metabolite that binds to proteins. In rodents, this leads to mitochondrial dysfunction and nuclear DNA fragmentation, resulting in necrotic cell death. While APAP metabolism is similar in humans, the later events resulting in toxicity have not been investigated in patients. In this study, levels of biomarkers of mitochondrial damage (glutamate dehydrogenase [GDH] and mitochondrial DNA [mtDNA]) and nuclear DNA fragments were measured in plasma from APAP-overdose patients. Overdose patients with no or minimal hepatic injury who had normal liver function tests (LTs) (referred to herein as the normal LT group) and healthy volunteers served as controls. Peak GDH activity and mtDNA concentration were increased in plasma from patients with abnormal LT. Peak nuclear DNA fragmentation in the abnormal LT cohort was also increased over that of controls. Parallel studies in mice revealed that these plasma biomarkers correlated well with tissue injury. Caspase-3 activity and cleaved caspase-3 were not detectable in plasma from overdose patients or mice, but were elevated after TNF-induced apoptosis, indicating that APAP overdose does not cause apoptosis. Thus, our results suggest that mitochondrial damage and nuclear DNA fragmentation are likely to be critical events in APAP hepatotoxicity in humans, resulting in necrotic cell death.

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“…The only substantial difference was the fact that these biomarkers had a shorter half-life in plasma compared to ALT suggesting again that these types of biomarkers reflect more accurately the injury process. However, these biomarkers were not detected in a mouse model of furosemide-induced liver injury, which does not involve mitochondrial damage [258] despite severe plasma ALT elevations and hepatocellular necrosis [164]. Thus, these biomarkers reflect more an injury mechanism than just cell death.…”

Section: Mitochondrial Biomarkers In Drug-induced Liver Injurymentioning

confidence: 99%

Mitochondrial dysfunction as a mechanism of drug-induced hepatotoxicity: current understanding and future perspectives

et al. 2018

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Mitochondria are critical cellular organelles for energy generation and are now also recognized as playing important roles in cellular signaling. Their central role in energy metabolism, as well as their high abundance in hepatocytes, make them important targets for drug-induced hepatotoxicity. This review summarizes the current mechanistic understanding of the role of mitochondria in drug-induced hepatotoxicity caused by acetaminophen, diclofenac, anti-tuberculosis drugs such as rifampin and isoniazid, anti-epileptic drugs such as valproic acid and constituents of herbal supplements such as pyrrolizidine alkaloids. The utilization of circulating mitochondrial-specific biomarkers in understanding mechanisms of toxicity in humans will also be examined. In summary, it is well-established that mitochondria are central to acetaminophen-induced cell death. However, the most promising areas for clinically useful therapeutic interventions after acetaminophen toxicity may involve the promotion of adaptive responses and repair processes including mitophagy and mitochondrial biogenesis, In contrast, the limited understanding of the role of mitochondria in various aspects of hepatotoxicity by most other drugs and herbs requires more detailed mechanistic investigations in both animals and humans. Development of clinically relevant animal models and more translational studies using mechanistic biomarkers are critical for progress in this area.

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The role of mitochondrial injury in bromobenzene and furosemide induced hepatotoxicity

Cited by 49 publications

References 24 publications

Protective Effects of Exogenous Glutathione and Related Thiol Compounds against Drug-Induced Liver Injury

Protective Effects of Exogenous Glutathione and Related Thiol Compounds against Drug-Induced Liver Injury

The mechanism underlying acetaminophen-induced hepatotoxicity in humans and mice involves mitochondrial damage and nuclear DNA fragmentation

Mitochondrial dysfunction as a mechanism of drug-induced hepatotoxicity: current understanding and future perspectives

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