Phenotypic-genotypic analysis of CYP2C19 in the Jewish Israeli population.

OBJECTIVES

Evaluation of CYP2C19 activity and the frequency of CYP2C19 alleles in the Jewish Israeli population.

METHODS

One hundred forty Jewish Israeli subjects received 100 mg racemic mephenytoin and collected urine for 8 hours. Urinary concentrations of mephenytoin enantiomers and 4'-hydroxymephenytoin were determined by gas-liquid chromatography and HPLC, respectively. CYP2C19 activity was derived from urinary S/R-ratio and 8-hour urinary excretion of 4'-hydroxymephenytoin. Mutations were identified by polymerase chain reaction and enzyme digestion with SmaI (CYP2C192) and BamHI (CYP2C193).

RESULTS

Deficient mephenytoin hydroxylation was found in 4 subjects (2.9%; 95% confidence interval [CI], 0.1% to 5.7%) who were homozygous for CYP2C192. CYP2C192 was the major deactivating allele accounting for 15% (95% CI, 11% to 19%) of CYP2C19 alleles, whereas CYP2C193 was identified in 2 subjects (1%; 95% CI, 0% to 2%). Among 136 extensive metabolizers, 99 were homozygous for CYP2C191 and 37 were compound heterozygous CYP2C191/CYP2C192 (35 subjects) or CYP2C191/CYP2C193 (2 subjects). Gene dose effect was noted so that the S/R-ratio was significantly greater and urinary excretion of 4'-hydroxymephenytoin was significantly lower in compound heterozygous than in homozygous extensive metabolizers (0.310+/-0.209 versus 0.225+/-0.176, P < .04 and 48.6%+/-19.2% versus 56.3%+/-16.0%, P < .03, respectively). Female extensive metabolizers had a significantly lower excretion of 4'-hydroxymephenytoin than male extensive metabolizers (49.5%+/-17.6% versus 58.4%+/-16.7%, respectively, P < .005).

CONCLUSION

The frequency of poor metabolizers of CYP2C19 and CYP2C19*2 allele in the Jewish Israeli population resembles findings in non-Asian populations. Complete concordance was noted between phenotypic and genotypic findings. CYP2C19 genotyping may enable subclassification of extensive metabolizers into subjects with high and low activity.