GENETIC ASSOCIATION BETWEEN SENSITIVITY TO WARFARIN AND EXPRESSION OFCYP2C9-ASTERISK-3

Cytochrome P4502C9 (CYP2C9) is largely responsible for terminating the anticoagulant effect of racemic warfarin via hydroxylation of the pha rmacologically more potent S-enantiomer to inactive metabolites, Mutat ions in the CYP2C9 gene result in the expression of three allelic vari ants, CYP2C91, CYP2C9*2 and CYP2C9*3. Both CYP2C9*2 and CYP2C9*3 exhi bit altered catalytic properties in vitro relative to the wild-type en zyme, In the present study, a patient was genotyped who had proven unu sually sensitive to warfarin therapy and could tolerate no more than 0 .5 mg of the racemic drug/day. PCR-amplification of exons 3 and 7 of t he CYP2C9 gene, followed by restriction digest or sequence analysis, s howed that this individual was homozygous for CYP2C93. In addition, p atient plasma warfarin enantiomer ratios and urinary 7-hydroxywarfarin enantiomer ratios were determined by chiral-phase high performance li quid chromotography in order to investigate whether either parameter m ight be of diagnostic value in place of a genotypic test. Control pati ents receiving 4-8 mg warfarin/day exhibited plasma S:R ratios of 0.50 +/- 0.25:1, whereas the patient on very low-dose warfarin exhibited a n S:R ratio of 3.9:1. In contrast, the urinary 7-hydroxywarfarin S:R r atio of 4:I showed the same stereoselectivity as that reported for con trol patients, Therefore, expression of CYP2C93 is associated with di minished clearance of S-warfarin and a dangerously exacerbated therape utic response to normal doses of the racemic drug, Analysis of the pla sma S:R warfarin ratio may serve as a useful alternative test to genot yping for this genetic defect.