The role of metabolic activation in drug toxicity.
Several xenobiotics undergo biotransformation reactions which yield reactive and potentially toxic compounds. Activation may occur via cytochrome P-450-mediated oxidation, prostaglandin synthetase-related hydroperoxidase-activity, or alcohol dehydrogenase/aldehyde dehydrogenase activity. The reactive metabolites thus formed may initiate lipid peroxidation or covalent binding to cell macromolecules, and secondarily lead to acute cytotoxicity or to tumorigenesis. Most cells possess mechanisms for protection against chemical toxicity, e.g. glutathione-related pathways and epoxide hydrolase activity. A possible strategy in handling toxic drug effects in the clinical situation may be chemotherapeutic manipulations aiming at a stimulation of protective mechanisms or at an inhibition of activating pathways.
D000082:Acetaminophen / Q000378:metabolism; D000818:Animals; D001711:Biotransformation; D055598:Chemical Phenomena; D002621:Chemistry; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D064420:Drug-Related Side Effects and Adverse Reactions; D004851:Epoxide Hydrolases / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008054:Lipid Peroxides / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism
D008054:Lipid Peroxides; D000082:Acetaminophen; D003577:Cytochrome P-450 Enzyme System; D009247:NADH, NADPH Oxidoreductases; D004851:Epoxide Hydrolases; D005978:Glutathione; D010100:Oxygen