Reactive Metabolite-Mediated Toxicity

Most foreign compounds are metabolized within the liver, and in general this process aids their elimination by converting relatively nonpolar compounds to more polar 

Quantitative determination of reactive metabolite formation can be achieved by determining irreversible covalent binding of radiolabeled test compound to proteins. The preferred test system for such studies is isolated human hepatocytes, which contain a broad variety of relevant enzymes and can be obtained commercially. Covalent binding studies provide invaluable information that can aid selection between potential lead series, or between short-listed 

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Chloroform causes kidney damage (proximal tubular necrosis) and liver damage (hepatic necrosis). The mechanism is believed to involve metabolic activation of the chloroform in the kidney to produce phosgene, which is probably responsible for the toxicity. Both liver and kidney damage may be modulated by treating animals with enzyme inducers and therefore it seems likely that the liver damage is also mediated by a reactive metabolite. 

Induction of the MPT requires Ca2+ conversely, plasma membrane and ER Ca2+ pumps require ATP. One of the earliest effects of CCb is metabolism-dependent inhibition of the ER Ca2+ pump through oxidation of a critical -SH residue. A similar oxidant-sensitive -SH residue is present in the plasma membrane Ca2+ pump. Thus, the reciprocal requirements of Ca2+ for the MPT and ATP for cellular Ca2+ pumps provide a mechanism for linkage of ATP depletion and disruption of Ca2+ homeostasis as mediators of cell death. Most proximal toxic effects that lead to hepatocellular mitochondrial and Ca2+ dysfunction can be generalized into two classes, those involving production of oxidative stress or formation of reactive metabolites. 

With the exception of some anticancer drugs, chemicals directly toxic to tissues are eliminated in the drug development process, so drug toxicity involving covalent binding usually is mediated by chemically reactive metabolites. Current mechanistic understanding of these toxic reactions usually extends to identification of the reactive metabolite and metabolic pathway involved. In some cases, protective mechanisms for... 

Because of the rare and unpredictable nature of hepatobihary reactions to terbinafine, the mechanism of hepatotoxicity has been hypothesized to be either immunological or metabolically mediated. A potentially toxic reactive metabolite of terbinafine, 7,7-dimethylhept-2-ene-4-jmal (TBF-A), the A-dealkylation product of terbinafine, has been identified in vitro (43). The authors speculated that this allylic aldehyde metabolite, formed by hver enzymes and conjugated with glutathione, would be transported across the canalicular membrane of hepatocytes and concentrated in the bile. The reactive monoglutathione conjugate could bind to hepatobiliary proteins and cause direct toxicity. Alternatively, it could modify canahcular proteins and lead to an immune-mediated reaction, causing cholestatic dysfunction. 

Allyl alcohol is inactive per se and its toxic effect is mediated by its ADH oxidation to form acrolein, which is responsible for the hepatotoxic action. The toxicity of the alcohol (or its metabolite acrolein) is dependent on the concentration of glutathione (GSH). After severe depletion of GSH, the reactive metabolite of allyl alcohol can bind to essential sulfhydryl groups in the cellular macromolecules, leading to structural and functional changes in cellular molecules, which can be responsible for cell death. In this case, the appearance of lipid peroxidation could be merely the consequence of cell death. 

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