Catalytic activities of human cytochrome P450 2C9*1, 2C9*3 and 2C9*13.
Cytochrome P450 2C9 (CYP2C9) is a geneticly polymorphic enzyme responsible for the metabolism of some clinically important drugs. CYP2C9*13 is an allele identified in a Chinese poor metabolizer of lornoxicam which has a Leu90Pro amino acid substitution. This paper reports on a study aimed at comparing the catalytic properties of CYP2C9*13 with those of the wild-type CYP2C9*1 and mutant CYP2C9*3 (Ile359Leu) in the COS-7 expression system using various substrates. CYP2C9*3 and *13 produced far lower luminescence than CYP2C9*1 in luciferin H metabolism. CYP2C9*13 exhibited an 11-fold increase in Km but no change in Vmax with tolbutamide as the substrate, a five-fold increase in Km and an 88.8% reduction in Vmax with diclofenac. These data indicate that CYP2C9*13 exhibits reduced metabolic activity toward all studied CYP2C9 substrates. The magnitude of the CYP2C9*13-associated decrease in intrinsic clearance (Vmax/Km) is greater than that associated with CYP2C9*3.
Guo
Y
Y
College of Life Science, Jilin University, Changchun, China.
Wang
Y
Y
Si
D
D
Fawcett
P J
PJ
Zhong
D
D
Zhou
H
H
D019943:Amino Acid Substitution; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D019556:COS Cells; D002522:Chlorocebus aethiops; D016861:Cyclooxygenase Inhibitors / Q000378:metabolism / Q000494:pharmacology; D065729:Cytochrome P-450 CYP2C9; D004008:Diclofenac / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000378:metabolism / Q000494:pharmacology; D007700:Kinetics; D017354:Point Mutation; D013379:Substrate Specificity / Q000235:genetics; D014044:Tolbutamide / Q000378:metabolism / Q000494:pharmacology
D016861:Cyclooxygenase Inhibitors; D007004:Hypoglycemic Agents; D004008:Diclofenac; D014044:Tolbutamide; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases