S Sviri1, S Shpizen, E Leitersdorf, M Levy, Y Caraco. 1. Division of Medicine, the Center of Research, Prevention and Treatment of Atherosclerosis, Hadassah University Hospital, Jerusalem, Israel.
Abstract
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 (CYP2C19*2) and BamHI (CYP2C19*3). RESULTS: Deficient mephenytoin hydroxylation was found in 4 subjects (2.9%; 95% confidence interval [CI], 0.1% to 5.7%) who were homozygous for CYP2C19*2. CYP2C19*2 was the major deactivating allele accounting for 15% (95% CI, 11% to 19%) of CYP2C19 alleles, whereas CYP2C19*3 was identified in 2 subjects (1%; 95% CI, 0% to 2%). Among 136 extensive metabolizers, 99 were homozygous for CYP2C19*1 and 37 were compound heterozygous CYP2C19*1/CYP2C19*2 (35 subjects) or CYP2C19*1/CYP2C19*3 (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.
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 (CYP2C19*2) and BamHI (CYP2C19*3). RESULTS: Deficient mephenytoin hydroxylation was found in 4 subjects (2.9%; 95% confidence interval [CI], 0.1% to 5.7%) who were homozygous for CYP2C19*2. CYP2C19*2 was the major deactivating allele accounting for 15% (95% CI, 11% to 19%) of CYP2C19 alleles, whereas CYP2C19*3 was identified in 2 subjects (1%; 95% CI, 0% to 2%). Among 136 extensive metabolizers, 99 were homozygous for CYP2C19*1 and 37 were compound heterozygous CYP2C19*1/CYP2C19*2 (35 subjects) or CYP2C19*1/CYP2C19*3 (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.
Authors: I Fricke-Galindo; C Céspedes-Garro; F Rodrigues-Soares; M E G Naranjo; Á Delgado; F de Andrés; M López-López; E Peñas-Lledó; A LLerena Journal: Pharmacogenomics J Date: 2015-10-27 Impact factor: 3.550
Authors: Mariana R Botton; Michelle Whirl-Carrillo; Andria L Del Tredici; Katrin Sangkuhl; Larisa H Cavallari; José A G Agúndez; Jorge Duconge; Ming Ta Michael Lee; Erica L Woodahl; Karla Claudio-Campos; Ann K Daly; Teri E Klein; Victoria M Pratt; Stuart A Scott; Andrea Gaedigk Journal: Clin Pharmacol Ther Date: 2020-07-22 Impact factor: 6.875