A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants.
OBJECTIVE
Many drugs, including proton pump inhibitors and certain antidepressants, are metabolized by the polymorphic cytochrome P450 (CYP) 2C19 enzyme. A significant portion of extensive metabolizers do not reach appropriate drug levels, and our objective was to investigate any genetic background.


METHODS
The 5'-flanking region of the CYP2C19 gene from subjects with rapid omeprazole metabolism was sequenced, and CYP2C19 phenotype-genotype associations were analyzed in Swedish (n = 107) and Ethiopian (n = 126) extensive metabolizers. The relationship of the metabolic ratio of omeprazole (omeprazole/5-hydroxyomeprazole in plasma 3 hours after drug intake) with the area under the plasma concentration-time curve was used for prediction studies. Electrophoretic mobility shift assays were conducted by use of human nuclear protein extracts. Hepatic reporter vector transfections were carried out in CD1 mice.


RESULTS
We identified a novel allele (CYP2C19*17) carrying -806C>T and -3402C>T, with a frequency of 18% in both Swedes and Ethiopians and 4% in Chinese subjects. In Swedes the metabolic ratio of omeprazole was higher in subjects homozygous for CYP2C19*1 (median, 0.50 [interquartile range, 0.37-0.73]) than in those homozygous for CYP2C19*17 (median, 0.25 [interquartile range, 0.15-0.33]) (P = .010). In Ethiopians a similar difference in the S/R-mephenytoin ratio was observed between individuals homozygous for CYP2C19*1 (median, 0.20 [interquartile range, 0.12-0.37]) and those homozygous for CYP2C19*17 (median, 0.05 [interquartile range, 0.03-0.06]) (P = .013). Electrophoretic mobility shift assays showed specific binding of human hepatic nuclear proteins to an element carrying -806T but not -806C. Reporter vector experiments showed an increased transcriptional activity of the CYP2C19*17 allele in vivo in mice. Predictions revealed that CYP2C19*17 homozygotes would attain 35% to 40% lower omeprazole area under the plasma concentration-time curve values than subjects homozygous for CYP2C19*1 taking standard doses of omeprazole.


CONCLUSIONS
CYP2C19*17 is likely to cause therapeutic failures in drug treatment with, for example, proton pump inhibitors and antidepressants.
Sim
Sarah C
SC
Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm. Sarah.Sim@ki.se
Risinger
Carl
C
Dahl
Marja-Liisa
ML
Aklillu
Eleni
E
Christensen
Magnus
M
Bertilsson
Leif
L
Ingelman-Sundberg
Magnus
M
D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics; D000928:Antidepressive Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D002681:China / Q000453:epidemiology; D065731:Cytochrome P-450 CYP2C19; D024202:Electrophoretic Mobility Shift Assay; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005002:Ethiopia / Q000453:epidemiology; D005787:Gene Frequency; D017930:Genes, Reporter / Q000235:genetics; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008617:Mephenytoin / Q000493:pharmacokinetics; D051379:Mice; D006899:Mixed Function Oxygenases / Q000235:genetics*; D009154:Mutation; D009853:Omeprazole / Q000493:pharmacokinetics / Q000627:therapeutic use; D010641:Phenotype; D010957:Plasmids / Q000235:genetics; D054328:Proton Pump Inhibitors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013548:Sweden / Q000453:epidemiology; D014162:Transfection
D000927:Anticonvulsants; D000928:Antidepressive Agents; D004791:Enzyme Inhibitors; D054328:Proton Pump Inhibitors; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D009853:Omeprazole; D008617:Mephenytoin