Activation mechanisms to chemical toxicity.
The pathobiology of chemical toxicity may involve "acute lethal injury" (necrosis), "autoxidative injury" (oxygen toxicity), "immunological injury" (neoantigen formation), and malignancy. Toxic chemicals may be activated by reduction, conjugation, radical formation, or oxidation. Oxidative activation may be effected by cytochromes P-450/P-448, flavoprotein monooxygenases, or hydroxyl radicals. The alternative pathways of oxidative metabolism of toxic chemicals, namely, detoxication and activation, are catalysed by the phenobarbital-induced cytochromes P-450 and by the 3-methylcholanthrene-induced cytochromes P-448 respectively. Oxidative metabolism by cytochromes P-450 is followed by conjugation and detoxication, whereas oxidative metabolism by cytochromes P-448 yields reactive intermediates which are not readily conjugated, and thus react with vital intracellular macromolecules, resulting in necrosis, redox cycling and oxygen radical formation, neoantigen production, and mutations. The molecular dimensions of specific substrates, inhibitors and inducers of the PB-cytochromes P-450 indicate that they are globular and are different from those of the cytochromes P-448 which are planar, suggesting that the active sites of the two families of enzymes are different. Oxidative metabolism of planar substrates of cytochromes P-448 results in conformationally-hindered oxygenations, which inhibits subsequent conjugations. Cytochrome P-448 activity may be quantified by the oxidative deethylation of 7-ethoxyresorufin which, unlike benzo(a)pyrene hydroxylation (AHH) is a specific reaction for this family of enzymes. Oxidative metabolism of chemicals varies inversely with the body weight of the animal species, so that chemical toxicity involving oxidative activation, redox cycling, and reactive oxygen is greater the smaller the animal species.
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D000818:Animals; D001711:Biotransformation; D003580:Cytochromes / Q000378:metabolism; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D004364:Pharmaceutical Preparations / Q000378:metabolism
D003580:Cytochromes; D004364:Pharmaceutical Preparations