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CYP2C19 activity comparison between Swedes and Koreans: effect of genotype, sex, oral contraceptive use, and smoking

  • Pharmacogenetics
  • Published:
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Abstract

Objectives

To compare CYP2C19 enzyme activity between Swedes and Koreans controlling for the effect of CYP2C19 genotype, sex, oral contraceptive use, and smoking habits.

Methods

CYP2C19 activity was determined in 185 healthy Swedish and 150 Korean subjects as the omeprazole/5-hydroxyomeprazole ratio (metabolic ratio; MR) using high-performance liquid chromatography. Genotyping was performed by PCR using Taqman assay.

Results

As expected, a higher incidence of poor metabolizers (PM) was found in Koreans (14%) compared with Swedes (3.8%) and the frequency of the CYP2C19*17 allele was very low in Koreans (0.3%). Among subjects homozygous for CYP2C19*1, Koreans displayed significantly lower CYP2C19 enzyme activity than Swedes (p < 0.000001). Interestingly, in Koreans a pronounced gender difference was apparent: females (n = 24) had significantly lower MR than males (n = 30; p < 0.0001), but such a gender difference was not seen among Swedes. Swedish OC users had a higher MR than non-users (p < 0.00001), whereas OC was only used by one Korean. No effects of smoking were observed.

Conclusions

We find specific gender-dependent effects of CYP2C19 activity in Koreans, but not in Swedes. Controlling for the effect of genotype and sex, Koreans display lower CYP2C19 activity than Swedes. The genetic, epigenetic or environmental basis for this difference remains to be identified.

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References

  1. Brosen K (2004) Some aspects of genetic polymorphism in the biotransformation of antidepressants. Therapie 59(1):5–12

    Article  PubMed  Google Scholar 

  2. Bertilsson L, Henthorn TK, Sanz E, Tybring G, Sawe J, Villen T (1989) Importance of genetic factors in the regulation of diazepam metabolism: relationship to S-mephenytoin, but not debrisoquin, hydroxylation phenotype. Clin Pharmacol Ther 45(4):348–355

    CAS  PubMed  Google Scholar 

  3. Ward SA, Helsby NA, Skjelbo E, Brosen K, Gram LF, Breckenridge AM (1991) The activation of the biguanide antimalarial proguanil co-segregates with the mephenytoin oxidation polymorphism—a panel study. Br J Clin Pharmacol 31(6):689–692

    CAS  PubMed  Google Scholar 

  4. Li XQ, Andersson TB, Ahlstrom M, Weidolf L (2004) Comparison of inhibitory effects of the proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities. Drug Metab Dispos 32(8):821–827

    Article  CAS  PubMed  Google Scholar 

  5. Andersson T, Miners JO, Veronese ME, Tassaneeyakul W, Meyer UA, Birkett DJ (1993) Identification of human liver cytochrome P450 isoforms mediating omeprazole metabolism. Br J Clin Pharmacol 36(6):521–530

    CAS  PubMed  Google Scholar 

  6. Laine K, Tybring G, Bertilsson L (2000) No sex-related differences but significant inhibition by oral contraceptives of CYP2C19 activity as measured by the probe drugs mephenytoin and omeprazole in healthy Swedish white subjects. Clin Pharmacol Ther 68(2):151–159

    Article  CAS  PubMed  Google Scholar 

  7. Chang M, Dahl ML, Tybring G, Gotharson E, Bertilsson L (1995) Use of omeprazole as a probe drug for CYP2C19 phenotype in Swedish Caucasians: comparison with S-mephenytoin hydroxylation phenotype and CYP2C19 genotype. Pharmacogenetics 5(6):358–363

    Article  CAS  PubMed  Google Scholar 

  8. Alvan G, Bechtel P, Iselius L, Gundert-Remy U (1990) Hydroxylation polymorphisms of debrisoquine and mephenytoin in European populations. Eur J Clin Pharmacol 39(6):533–537

    Article  CAS  PubMed  Google Scholar 

  9. Jurima M, Inaba T, Kadar D, Kalow W (1985) Genetic polymorphism of mephenytoin p(4′)-hydroxylation: difference between Orientals and Caucasians. Br J Clin Pharmacol 19(4):483–487

    CAS  PubMed  Google Scholar 

  10. Nakamura K, Goto F, Ray WA, McAllister CB, Jacqz E, Wilkinson GR, Branch RA (1985) Interethnic differences in genetic polymorphism of debrisoquin and mephenytoin hydroxylation between Japanese and Caucasian populations. Clin Pharmacol Ther 38(4):402–408

    CAS  PubMed  Google Scholar 

  11. Horai Y, Nakano M, Ishizaki T, Ishikawa K, Zhou HH, Zhou BI, Liao CL, Zhang LM (1989) Metoprolol and mephenytoin oxidation polymorphisms in Far Eastern Oriental subjects: Japanese versus mainland Chinese. Clin Pharmacol Ther 46(2):198–207

    CAS  PubMed  Google Scholar 

  12. Bertilsson L, Lou YQ, Du YL, Liu Y, Kuang TY, Liao XM, Wang KY, Reviriego J, Iselius L, Sjoqvist F (1992) Pronounced differences between native Chinese and Swedish populations in the polymorphic hydroxylations of debrisoquin and S-mephenytoin. Clin Pharmacol Ther 51(4):388–397

    CAS  PubMed  Google Scholar 

  13. Ishizaki T, Sohn DR, Kobayashi K, Chiba K, Lee KH, Shin SG, Andersson T, Regardh CG, Lou YC, Zhang Y et al (1994) Interethnic differences in omeprazole metabolism in the two S-mephenytoin hydroxylation phenotypes studied in Caucasians and Orientals. Ther Drug Monit 16(2):214–215

    Article  CAS  PubMed  Google Scholar 

  14. Roh HK, Dahl ML, Tybring G, Yamada H, Cha YN, Bertilsson L (1996) CYP2C19 genotype and phenotype determined by omeprazole in a Korean population. Pharmacogenetics 6(6):547–551

    Article  CAS  PubMed  Google Scholar 

  15. De Morais SM, Wilkinson GR, Blaisdell J, Nakamura K, Meyer UA, Goldstein JA (1994) The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans. J Biol Chem 269(22):15419–15422

    PubMed  Google Scholar 

  16. De Morais SM, Wilkinson GR, Blaisdell J, Meyer UA, Nakamura K, Goldstein JA (1994) Identification of a new genetic defect responsible for the polymorphism of (S)-mephenytoin metabolism in Japanese. Mol Pharmacol 46(4):594–598

    PubMed  Google Scholar 

  17. Sim SC, Risinger C, Dahl ML, Aklillu E, Christensen M, Bertilsson L, Ingelman-Sundberg M (2006) A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants. Clin Pharmacol Ther 79(1):103–113

    Article  CAS  PubMed  Google Scholar 

  18. Sandberg M, Johansson I, Christensen M, Rane A, Eliasson E (2004) The impact of CYP2C9 genetics and oral contraceptives on cytochrome P450 2C9 phenotype. Drug Metab Dispos 32(5):484–489

    Article  CAS  PubMed  Google Scholar 

  19. Djordjevic N, Ghotbi R, Bertilsson L, Jankovic S, Aklillu E (2008) Induction of CYP1A2 by heavy coffee consumption in Serbs and Swedes. Eur J Clin Pharmacol 64(4):381–385

    Article  CAS  PubMed  Google Scholar 

  20. Ghotbi R, Christensen M, Roh HK, Ingelman-Sundberg M, Aklillu E, Bertilsson L (2007) Comparisons of CYP1A2 genetic polymorphisms, enzyme activity and the genotype-phenotype relationship in Swedes and Koreans. Eur J Clin Pharmacol 63(6):537–546

    Article  CAS  PubMed  Google Scholar 

  21. Christensen M, Andersson K, Dalen P, Mirghani RA, Muirhead GJ, Nordmark A, Tybring G, Wahlberg A, Yasar U, Bertilsson L (2003) The Karolinska cocktail for phenotyping of five human cytochrome P450 enzymes. Clin Pharmacol Ther 73(6):517–528

    Article  CAS  PubMed  Google Scholar 

  22. Tybring G, Bottiger Y, Widen J, Bertilsson L (1997) Enantioselective hydroxylation of omeprazole catalyzed by CYP2C19 in Swedish white subjects. Clin Pharmacol Ther 62(2):129–137

    Article  CAS  PubMed  Google Scholar 

  23. Xie HG, Huang SL, Xu ZH, Xiao ZS, He N, Zhou HH (1997) Evidence for the effect of gender on activity of (S)-mephenytoin 4′-hydroxylase (CYP2C19) in a Chinese population. Pharmacogenetics 7(2):115–119

    Article  CAS  PubMed  Google Scholar 

  24. Gomez A, Ingelman-Sundberg M (2009) Pharmacoepigenetics: its role in interindividual differences in drug response. Clin Pharmacol Ther 85(4):426–430

    Article  CAS  PubMed  Google Scholar 

  25. Kim JI, Ju YS, Park H, Kim S, Lee S, Yi JH, Mudge J, Miller NA, Hong D, Bell CJ, Kim HS, Chung IS, Lee WC, Lee JS, Seo SH, Yun JY, Woo HN, Lee H, Suh D, Kim HJ, Yavartanoo M, Kwak M, Zheng Y, Lee MK, Kim JY, Gokcumen O, Mills RE, Zaranek AW, Thakuria J, Wu X, Kim RW, Huntley JJ, Luo S, Schroth GP, Wu TD, Kim H, Yang KS, Park WY, Church GM, Lee C, Kingsmore SF, Seo JS (2009) A highly annotated whole-genome sequence of a Korean individual. Nature 460(7258):1011–1015

    CAS  PubMed  Google Scholar 

  26. Tamminga WJ, Wemer J, Oosterhuis B, Weiling J, Wilffert B, de Leij LF, de Zeeuw RA, Jonkman JH (1999) CYP2D6 and CYP2C19 activity in a large population of Dutch healthy volunteers: indications for oral contraceptive-related gender differences. Eur J Clin Pharmacol 55(3):177–184

    Article  CAS  PubMed  Google Scholar 

  27. Hagg S, Spigset O, Dahlqvist R (2001) Influence of gender and oral contraceptives on CYP2D6 and CYP2C19 activity in healthy volunteers. Br J Clin Pharmacol 51(2):169–173

    Article  CAS  PubMed  Google Scholar 

  28. Palovaara S, Tybring G, Laine K (2003) The effect of ethinyloestradiol and levonorgestrel on the CYP2C19-mediated metabolism of omeprazole in healthy female subjects. Br J Clin Pharmacol 56(2):232–237

    Article  CAS  PubMed  Google Scholar 

  29. Suzuki T, Matsuo K, Sawaki A, Wakai K, Hirose K, Ito H, Saito T, Nakamura T, Yamao K, Hamajima N, Tajima K (2007) Influence of smoking and CYP2C19 genotypes on H. pylori eradication success. Epidemiol Infect 135(1):171–176

    Article  CAS  PubMed  Google Scholar 

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Acknowledgement

The study was financially supported by the Swedish Research Council, Medicine, 3902 and the Swedish Capio Forskningsstiftelse.

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Correspondence to Eleni Aklillu.

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Ramsjö, M., Aklillu, E., Bohman, L. et al. CYP2C19 activity comparison between Swedes and Koreans: effect of genotype, sex, oral contraceptive use, and smoking. Eur J Clin Pharmacol 66, 871–877 (2010). https://doi.org/10.1007/s00228-010-0835-0

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  • DOI: https://doi.org/10.1007/s00228-010-0835-0

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