Evaluation of microsomal pathways of oxidation of alcohols and hydroxyl radical scavenging agents with carbon monoxide and cobalt protoporphyrin IX.

Rat liver microsomes catalyze the oxidation of hydroxyl radical scavenging agents by an iron-dependent process, and can oxidize alcohols by pathways dependent on, as well as independent of, .OH. Experiments were carried out to evaluate which microsomal components participate in the production of .OH, and in the two pathways of oxidation of alcohols. Cobalt protoporphyrin IX treatment of rats resulted in a decrease in microsomal oxidation of aminopyrine, .OH scavengers, and alcohols. However, this treatment not only lowered the content of cytochrome P-450, but also decreased the activity of NADPH-cytochrome P-450 reductase. Carbon monoxide, metyrapone and SKF-525A also inhibited the oxidation of aminopyrine but did not affect oxidation of .OH scavengers. Desferrioxamine, a potent iron chelator, inhibited the oxidation of .OH scavengers but not aminopyrine. The oxidation of alcohols was partly sensitive to desferrioxamine and partly sensitive to carbon monoxide, thus showing similarities to the oxidation of .OH scavengers and drugs. These results suggest that the desferrioxamine-sensitive, .OH-dependent pathway of alcohol oxidation is mediated by the reductase, in analogy to results with .OH scavengers, whereas the desferrioxamine-resistant pathway of alcohol oxidation is mediated by cytochrome P-450, in analogy to results with aminopyrine. By the use of desferrioxamine or carbon monoxide, either of the two alcohol-oxidizing pathways can be inhibited independently of each other.