1. ¹Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm
2. ²ARA Life Science AB and Department of Medical Sciences, Clinical Pharmacology, University Hospital, Uppsala
3. ³Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska University Hospital, Karolinska Institutet, Huddinge, Sweden

Correspondence: Sarah C. Sim, MSc, Division of Physiology and Pharmacology, IMM, Karolinska Institutet, SE-171 77 Stockholm, Sweden E-mail: Sarah.Sim@ki.se

^*This work was supported by grants from the Swedish Research Council (5949 and 3902) and the National Institutes of Health (NIGMS 1-R01 GM60548).

Received 22 August 2005; Accepted 10 October 2005.

Abstract

Background and 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.

Conclusion: CYP2C19*17 is likely to cause therapeutic failures in drug treatment with, for example, proton pump inhibitors and antidepressants.