Mechanisms and Outcomes of Drug- and Toxicant-Induced Liver Toxicity in Diabetes

Wang, T.; Shankar, Kartik; Ronis, Martin J. J.; Mehendale, Harihara M.

doi:10.1080/10408440701215100

Cited by 59 publications

(38 citation statements)

References 368 publications

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“…Potential mechanisms that favor increased susceptibility of steatotic liver to drug-induced toxicity include mitochondrial imbalance [107] , increased mitochondrial ROS production [108] , and deficient repair capacity [109] . Indeed, a high incidence of hepatotoxicity has been observed in patients with type 2 diabetes [110] , a condition that is associated inevitably with fatty liver [111] . Therefore, it is conceivable that hepatotoxic drugs might produce injury even at non-toxic doses in patients with fatty liver, although in a recent study [112] , steatosis appeared to protect against paracetamol toxicity through preserving microcirculatory alterations.…”

Section: Future Perspectivesmentioning

confidence: 99%

Biochemical mechanisms in drug-induced liver injury: Certainties and doubts

Grattagliano

Bonfrate

Diogo

et al. 2009

WJG

123

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Drug-induced liver injury is a significant and still unresolved clinical problem. Limitations to knowledge about the mechanisms of toxicity render incomplete the detection of hepatotoxic potential during preclinical development. Several xenobiotics are lipophilic substances and their transformation into hydrophilic compounds by the cytochrome P-450 system results in production of toxic metabolites. Aging, preexisting liver disease, enzyme induction or inhibition, genetic variances, local O 2 supply and, above all, the intrinsic molecular properties of the drug may affect this process. Necrotic death follows antioxidant consumption and oxidation of intracellular proteins, which determine increased permeability of mitochondrial membranes, loss of potential, decreased ATP synthesis, inhibition of Ca 2+ -dependent ATPase, reduced capability to sequester Ca 2+ within mitochondria, and membrane bleb formation. Conversely, activation of nucleases and energetic participation of mitochondria are the main intracellular mechanisms that lead to apoptosis. Non-parenchymal hepatic cells are inducers of hepatocellular injury and targets for damage. Activation of the immune system promotes idiosyncratic reactions that result in hepatic necrosis or cholestasis, in which different HLA genotypes might play a major role. This review focuses on current knowledge of the mechanisms of drug-induced liver injury and recent advances on newly discovered mechanisms of liver damage. Future perspectives including new frontiers for research are discussed.

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Section: Future Perspectivesmentioning

confidence: 99%

Biochemical mechanisms in drug-induced liver injury: Certainties and doubts

Grattagliano

Bonfrate

Diogo

et al. 2009

WJG

123

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“…Additionally, liver is the most vulnerable to toxic chemical agents (Wang et al, 2007;Bhondave et al, 2014). Acute liver injury typically causes rapid development of hepatocellular dysfunction and has a poor prognosis.…”

Section: Introductionmentioning

confidence: 99%

Carbon tetrachloride-induced lethality in mouse is prevented by multiple pretreatment with zinc sulfate

et al. 2016

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-Carbon tetrachloride (CCl 4 ) is commonly used as a chemical inducer of experimental liver injury. Several compounds have been demonstrated to attenuate the hepatic damage caused by sublethal doses of CCl 4 . However, rescue from lethal toxicity of CCl 4 has not been reported. In the present study, we evaluated the protective effect of metallothionein (MT), an endogenous scavenger of free radicals, on CCl 4 -induced lethal toxicity of mice. To induce MT production in male ddY mice, we administered Zn (as ZnSO 4 ) at 50 mg/kg as a once-daily subcutaneous injection for 3 days prior to a single intraperitoneal administration of 4 g/kg CCl 4 . Animals were observed for mortality every 3 hr for 24 hr after CCl 4 injection. Liver damage was assessed by determining (in a subset of these mice) blood levels of alanine aminotransferase (ALT; a marker of liver injury) and liver histopathology at 6 hr after CCl 4 injection. Our results showed that three times pretreatment with Zn yielded > 40-fold induction of hepatic MT protein levels compared to control group. Zn pretreatment completely abolished the CCl 4 -induced mortality of mice. We also found that pretreatment of mice with Zn significantly decreased the ALT levels and reduced the histological liver damage as assessed at 6 hr post-CCl 4 . These findings suggest that prophylaxis with Zn protects mice from CCl 4 -induced acute hepatic toxicity and mortality, presumably by induction of radical-scavenging MT.

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“…CCl 4 -induced hepatotoxicity is a multifactorial process. [4][5][6] The first step is the metabolic activation of CCl 4 by cytochrome P450 2E1 (CYP2E1), resulting in trichloromethyl and trichloromethyl peroxy radicals. The second step is radical binding: the free radicals react with the sulfhydryl groups of antioxidant enzymes (e.g., glutathione and protein thiols).…”

mentioning

confidence: 99%