Interindividual Variations in Xenobiotic-Oxidizing P450 Activities in Humans

Abstract

Multiple forms of cytochrome P450 (P450 or CYP) exist in several organs of humans and individual P450 isoforms have considerable, but overlapping, substrate specificities. CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 are identified to date to be the major P450 enzymes involved in the oxidation of xenobiotics including drugs, environmental chemicals, and carcinogens and CYP1A1 and CYP1B1 have been shown to be principally expressed in extrahepatic organs. Most of the xenobiotic chemicals which are ingested clinically or incidentally into the body have been shown to be oxidized by multiple forms of P450 in several organs such as liver, intestine, and lung. Roles of these P450 isoforms in the oxidation of xenobiotics have been shown to be determined by the ratio of V_max to K_m of the P450 isoforms and the levels of expression of these P450 forms in different human samples. Here we show our model studies involving the roles of several P450 enzymes in the oxidation of omeprazole, 7-ethoxycoumarin, and chlorzoxazone using kinetic parameters of recombinant P450 enzymes and contents of individual P450 forms in human liver microsomes. Future work which must be addressed to be examined will be briefly discussed.