Cellular redox changes and response to drugs and toxic agents.
Cellular metabolism and, in particular, oxidation-reduction systems are linked to responses to drugs and toxic agents in several ways. Major connections are given by the NADPH/NADP+ system and the GSH/GSSG system. Intracellular reductive pathways generally use NADPH as the electron donor. From a toxicological point of view, NADPH can be considered both as a "detoxicant" and as a "toxicant". In the former case, NADPH supports the glutathione redox cycle by maintaining a negative redox potential of GSH to permit its detoxication functions to occur. NADPH is also the main donor for reducing equivalents in drug oxidations by the cytochrome P-450-dependent monooxygenase system which, with some notable exceptions, serves important purposes in detoxication. The sources of NADPH reducing equivalents depend on the nutritional state: major sources in the fed state are represented by the cytosolic pentose phosphate shunt dehydrogenases, whereas mitochondrial sources linked to isocitrate dehydrogenase provide the bulk of NADPH reducing equivalents in the fasted state. As a "toxicant", NADPH supports redox cycling reactions involving various drugs and other compounds of quinoid structure, aromatic nitro compounds and iron chelates with formation of superoxide anion radicals and subsequent formation of other oxygen derived radical species. This presentation focuses on recent work carried out with isolated hepatocytes and perfused rat liver with respect to "oxidative stress". The noninvasive techniques of measurement of low-level chemiluminescence and of volatile hydrocarbons (ethane, pentane) as well as glutathione release and calcium release have been employed.
D000429:Alcohol Oxidoreductases / Q000378:metabolism; D000818:Animals; D001711:Biotransformation; D002118:Calcium / Q000378:metabolism; D005978:Glutathione / Q000031:analogs & derivatives / Q000378:metabolism; D019803:Glutathione Disulfide; D005979:Glutathione Peroxidase / Q000378:metabolism; D006454:Hemoglobins / Q000502:physiology; D006838:Hydrocarbons / Q000378:metabolism; D008658:Inactivation, Metabolic; D008054:Lipid Peroxides / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008163:Luminescent Measurements; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D051381:Rats
D006454:Hemoglobins; D006838:Hydrocarbons; D008054:Lipid Peroxides; D009249:NADP; D000429:Alcohol Oxidoreductases; D005979:Glutathione Peroxidase; D005978:Glutathione; D002118:Calcium; D019803:Glutathione Disulfide