[Roles of human cytochrome P450 enzymes involved in drug metabolism and toxicological studies].
Multiple forms of cytochrome P450 (P450 or CYP) enzymes play important roles in the oxidation of structurally diverse xenobiotics and endobiotics. Interindividual variations in the level and activity of P450 enzymes were investigated in the human liver microsomes. Although the total P450 content was higher in Caucasian samples than in Japanese ones, the relative levels (percentage of total P450) of individual forms of P450 determined immunochemically were not very different. CYP3A (about 30% of total P450) and CYP2C (about 20%) enzymes were major forms. Different P450 enzymes in the human liver play major roles in a variety of drug oxidations and the hepatic contents of these P450 forms could be affective to determine which P450 enzymes play major roles in drug metabolism in individual humans. Recently recombinant P450 enzymes from different sources, e.g., microsomes of human lymphoblastoid cells, of yeast, and insect cells infected with baculovirus systems, and Escherichia coli membranes containing coexpressed P450 and reductase, have been widely used for drug metabolism research. However, the marker activities or kinetic parameters of human P450 enzymes reported are not always similar. Cytochrome b5 can enhance the activities of recombinant P450 systems in some cases using different mechanisms. These differences in activities may be a critical factor for understanding the roles of human P450 enzymes involved in drug metabolism. This review provides useful information for the study of drug biotransformation in humans and for the basis of drug toxicities and carcinogenesis.
Yamazaki
H
H
Division of Drug Metabolism, Faculty of Pharmaceutical Sciences, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-0934, Japan.
D001189:Aryl Hydrocarbon Hydroxylases; D002384:Catalysis; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism / Q000502:physiology; D015786:Cytochromes b5 / Q000502:physiology; D004347:Drug Interactions; D006801:Humans; D008658:Inactivation, Metabolic; D008862:Microsomes, Liver / Q000201:enzymology; D010084:Oxidation-Reduction; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D015262:Xenobiotics / Q000493:pharmacokinetics
D015262:Xenobiotics; D015786:Cytochromes b5; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating