Inhibition of microsomal oxidation of alcohols and of hydroxyl-radical-scavenging agents by the iron-chelating agent desferrioxamine.
Rat liver microsomes (microsomal fractions) catalyse the oxidation of straight-chain aliphatic alcohols and of hydroxyl-radical-scavenging agents during NADPH-dependent electron transfer. The iron-chelating agent desferrioxamine, which blocks the generation of hydroxyl radicals in other systems, was found to inhibit the following microsomal reactions: production of formaldehyde from either dimethyl sulphoxide or 2-methylpropan-2-ol (t-butylalcohol); generation of ethylene from 4-oxothiomethylbutyric acid; release of 14CO2 from [I-14C]benzoate; production of acetaldehyde from ethanol or butanal (butyraldehyde) from butan-1-ol. Desferrioxamine also blocked the increase in the oxidation of all these substrates produced by the addition of iron-EDTA to the microsomes. Desferrioxamine had no effect on a typical mixed-function-oxidase activity, the N-demethylation of aminopyrine, nor on the peroxidatic activity of catalase/H2O2 with ethanol. H2O2 appears to be the precursor of the oxidizing radical responsible for the oxidation of the alcohols and the other hydroxyl-radical scavengers. Chelation of microsomal iron by desferrioxamine most likely decreases the generation of hydroxyl radicals, which results in an inhibition of the oxidation of the alcohols and the hydroxyl-radical scavengers. Whereas desferrioxamine inhibited the oxidation of 2-methylpropan-2-ol, dimethyl sulphoxide, 4-oxothiomethylbutyrate and benzoate by more than 90%, the oxidation of ethanol and butanol could not be decreased by more than 45-60%. Higher concentrations of desferrioxamine were required to block the metabolism of the primary alcohols than to inhibit the metabolism of the other substrates. The desferrioxamine-insensitive rate of oxidation of ethanol was not inhibited by competitive hydroxyl-radical scavengers. These results suggest that primary alcohols may be oxidized by two pathways in microsomes, one dependent on the interaction of the alcohols with hydroxyl radicals (desferrioxamine-sensitive), the other which appears to be independent of these radicals (desferrioxamine-insensitive).
D000438:Alcohols / Q000378:metabolism*; D000632:Aminopyrine / Q000378:metabolism; D000818:Animals; D001565:Benzoates / Q000378:metabolism; D019817:Benzoic Acid; D003676:Deferoxamine / Q000494:pharmacology*; D004121:Dimethyl Sulfoxide / Q000378:metabolism; D004492:Edetic Acid / Q000494:pharmacology; D005290:Ferric Compounds / Q000494:pharmacology; D006878:Hydroxides / Q000378:metabolism*; D017665:Hydroxyl Radical; D066298:In Vitro Techniques; D008297:Male; D008715:Methionine / Q000031:analogs & derivatives / Q000378:metabolism; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains
D000438:Alcohols; D001565:Benzoates; D005290:Ferric Compounds; D006878:Hydroxides; D000632:Aminopyrine; D017665:Hydroxyl Radical; C014632:2-keto-4-methylthiobutyric acid; D019817:Benzoic Acid; D004492:Edetic Acid; D008715:Methionine; D003676:Deferoxamine; C019179:Fe(III)-EDTA; D004121:Dimethyl Sulfoxide