Oxygen activation during drug metabolism.
The peroxidase-H2O2 catalyzed oxidation of certain drugs in the presence of GSH resulted in extensive oxidation to thiyl radicals and GSSG. NADH or arachidonate in place of GSH was also readily oxidized. Extensive oxygen uptake ensued resulting in the formation of superoxide radicals and H2O2. Only catalytic amounts of drugs and low peroxide levels were required, indicating a radox cycling mechanism. Active drugs included morphine, phenothiazines, aminopyrine, p-phenetidine, acetaminophen and 4-N,N-(CH3)2-aminophenol. Other drugs, including dopamine and methyl-alpha-dopa, did not catalyze oxygen uptake, nor was GSH oxidized to GSSG. Instead, GSH was depleted by GSH conjugate formation. Drugs of the former group, e.g. acetaminophen, aminopyrine or N,N-(CH3)2-aniline, have also been found by other investigators to form GSSG and hydrogen peroxide when added to hepatocytes or when perfused through an isolated liver. Although cytochrome P-450 normally catalyzes a two-electron oxidation of drugs, serious consideration should be given to some one-electron oxidation occurring as well and resulting in radical formation, oxygen activation and GSSG formation.
D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D001711:Biotransformation; D005978:Glutathione / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D010084:Oxidation-Reduction; D010101:Oxygen Consumption; D010544:Peroxidases / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D051381:Rats; D013482:Superoxide Dismutase / Q000378:metabolism
D001095:Arachidonic Acids; D004364:Pharmaceutical Preparations; D009243:NAD; D016718:Arachidonic Acid; D010544:Peroxidases; D013482:Superoxide Dismutase; D005978:Glutathione