A common novel CYP2C19 gene variant
causes ultrarapid drug metabolism relevant
for the drug response to proton pump
inhibitors and antidepressants
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 back-
ground.
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 Ethi-
opian (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 Ethio-
pians 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 (me-
dian, 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. Predic-
tions 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. (Clin Pharmacol Ther 2006;79:103–13.)
Sarah C. Sim, MSc, Carl Risinger, PhD, Marja-Liisa Dahl, MD, PhD,
Eleni Aklillu, PhD, Magnus Christensen, MD, PhD, Leif Bertilsson, PhD, and
Magnus Ingelman-Sundberg, BScM, PhD Stockholm, Uppsala, and Huddinge, Sweden
Cytochrome P450s (CYPs) are responsible for about
80% of all phase I– dependent metabolism of clinically
used drugs, and the polymorphic CYP2C9, CYP2C19,
and CYP2D6 enzymes metabolize about 30% to 40%
of these.
1
Efficient substrates for CYP2C19 are, for
example, proton pump inhibitors (PPIs); antidepres-
From the Division of Molecular Toxicology, Institute of Environ-
mental Medicine, Karolinska Institutet, Stockholm; ARA Life Sci-
ence AB and Department of Medical Sciences, Clinical Pharma-
cology, University Hospital, Uppsala; and Department of
Laboratory Medicine, Division of Clinical Pharmacology, Karo-
linska University Hospital, Karolinska Institutet, Huddinge.
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 for publication Aug 22, 2005; accepted Oct 10, 2005.
Reprint requests: Sarah C. Sim, MSc, Division of Physiology and
Pharmacology, IMM, Karolinska Institutet, SE-171 77 Stockholm,
Sweden.
E-mail: Sarah.Sim@ki.se
0009-9236/$32.00
Copyright © 2006 by the American Society for Clinical Pharmacology
and Therapeutics.
doi:10.1016/j.clpt.2005.10.002
103