Possible Role of P-450 in the Oxidation of Drugs in Liver Microsomes

抄録

It was postulated from evidence obtained in the present studies that liver microsomal cytochrome binding carbon monoxide, pro- visionally called P-450, may act as an oxygen-activating component in the oxida-tion of drugs in microsomes.
1. The administration of phenobarbital to rats increased the amount of P-450 in liver microsomes and this found to be increase was almost parallel to that of drug oxidation activity.
2. Starvation caused a slight increase in the amount of P-450, while a sucrose diet caused a decrease. The effect of pheno-barbital in increasing the amount of P-450 was greatly increased in fasting rats. These changes in P-450 were similar to those in oxidation activity.
3. There was little or no P-450 in the liver of the fetus and new-born rats but the amout increased progressively up to 30 days of age and decreased again late. These changes are also similar to the changes in drug oxidation activity.
4. The amount of P-450 was highest in the liver and very low in the kidney and lung. It was negligibly small in the brain, muscle and heart.
Drug oxidation activity also varied in the some way.
5. Administration of phenobarbital and various other compounds increased the amount of P-450 and the degree of this increase was parallel to that of drug oxida-tion activity.
6. In a survey of the distributions of P-450 and drug oxidation activity in different animals the amount of P-450 was found to be highest in the liver of the mouse and lowest in the liver of the cats and drug oxidation activity varied similarly.
6. Drug oxidation activity was inhibited by increase in the concentration of carbon monoxide in the atmosphere and this inhibi-tion was in parallel to the decrease in the amount of free P-450.
Based on these results as well as on the nature of P-450, a possible mechanism for the oxidation of drugs was proposed.