2005
DOI: 10.1146/annurev.pharmtox.45.120403.100058
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The Role of Metabolic Activation in Drug-Induced Hepatotoxicity

Abstract: The importance of reactive metabolites in the pathogenesis of drug-induced toxicity has been a focus of research interest since pioneering investigations in the 1950s revealed the link between toxic metabolites and chemical carcinogenesis. There is now a great deal of evidence that shows that reactive metabolites are formed from drugs known to cause hepatotoxicity, but how these toxic species initiate and propagate tissue damage is still poorly understood. This review summarizes the evidence for reactive metab… Show more

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Cited by 421 publications
(309 citation statements)
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“…Taken together, these findings strongly suggest that the difference in AUC between radioactivity and osimertinib, AZ5104, and AZ7550 is due to osimertinib-related material bound to plasma proteins, especially albumin. No findings in the clinical or preclinical studies to date indicate that covalent binding of osimertinib and/or its metabolites to proteins is associated with any toxicologic sequelae, such as idiosyncratic liver or immune-mediated toxicity (Zhou et al, 2005;Park et al, 2005). In humans, the most abundant circulating metabolites observed in steady-state plasma extracts from patients dosed with non-radiolabeled osimertinib at 80 mg were AZ5104 (N-demethylation on the indole) and AZ7550 (N-demethylation on the dimethyl amine), representing 8% and 6% of total drug-related material, respectively.…”
Section: Discussionmentioning
confidence: 99%
“…Taken together, these findings strongly suggest that the difference in AUC between radioactivity and osimertinib, AZ5104, and AZ7550 is due to osimertinib-related material bound to plasma proteins, especially albumin. No findings in the clinical or preclinical studies to date indicate that covalent binding of osimertinib and/or its metabolites to proteins is associated with any toxicologic sequelae, such as idiosyncratic liver or immune-mediated toxicity (Zhou et al, 2005;Park et al, 2005). In humans, the most abundant circulating metabolites observed in steady-state plasma extracts from patients dosed with non-radiolabeled osimertinib at 80 mg were AZ5104 (N-demethylation on the indole) and AZ7550 (N-demethylation on the dimethyl amine), representing 8% and 6% of total drug-related material, respectively.…”
Section: Discussionmentioning
confidence: 99%
“…[50][51][52] Doxorubicin and tamoxifen are cancer chemotherapeutics and have been cited for in vivo and in vitro hepatoxicities, presumably due to oxidative stress. 53,54 Methylmercury chloride, phenylmercuric acetate, and mercury chloride are mercury-containing compounds that have been well established as an environmental toxins and public health risks. 55,56 Despite the fact that no definitive primary mechanism of toxicity has been reported, a range of potential mechanisms have been proposed, such as mitochondrial dysfunction, lipid peroxidation, microtubule disruption, and oxidative stress.…”
Section: Cytotoxicity Of Chemical Compoundsmentioning
confidence: 99%
“…1999; Boelsterli 2003; Park et al. 2005). In addition, diclofenac is able to induce direct mitochondrial dysfunction (Begriche et al.…”
Section: Introductionmentioning
confidence: 99%