Pharmacogenetics and polymorphism of human P-450 which activates and detoxicates xenobiotics and carcinogens

Abstract

Stereoselective hydroxylation of mephenytoin is expressed polymorphically in the Japanese population: the occurrence of the poor metabolizer was approximately 20% in Japanese, which was 5 to 8 times higher than that in Caucasians. Microsomal 4'-hydroxylation of S-mephenytoin, but not of R-mephenytoin, was correlated to the content of cytochrome P-450 human-2. P-450 human-2 cDNA was cloned and expressed in yeast cells. The expressed P-450 showed stereoselectivities similar to those in human livers for hydroxylations of mephenytoin and hexobarbital enantiomers. The P-450 catalyzed benzo[a]pyrene and tolbutamide hydroxylations and cyclophosphamide oxidation, but showed low activity for the mutagenic activation of IQ (2-amino-3-methylimidazo [4, 5-f]quinoline). Two cDNAs (MP-8 and lambda hPA6), which are two amino acids mutated and deleted, respectively, from P-450 human-2 cDNA were expressed in yeasts. These two expressed P-450s revealed complete loss of the stereoselectivity in the hydroxylation of mephenytoin and hexobarbital. These results indicate that many xenobiotics and carcinogens are detoxicated and activated by the human liver in quite different manners among individuals by reason of genetic differences.