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Limited effects of frequent CYP2D6*36-*10 tandem duplication allele on in vivo dextromethorphan metabolism in a Japanese population

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Abstract

Purpose

Although CYP2D6*36 was thought to be one of the alleles causing the poor metabolizer phenotype, several in vitro studies clarified that the enzyme produced by CYP2D6*36 showed enzymatic activities. However, the effects of CYP2D6*36 in tandem with CYP2D6*10 on the in vivo CYP2D6 activity have been unclear. In this study, we investigated in vivo metabolic capacities of CYP2D6 among the subjects carrying different numbers of CYP2D6*36 in tandem with CYP2D6*10.

Methods

We measured the metabolic ratio (MR) of dextromethorphan in 98 subjects. We determined the CYP2D6 genotype of these subjects, including allelic copy number of CYP2D6*10 and CYP2D6*36 by direct sequencing, TaqMan assay, and real-time Invader assay.

Results

Single copies of CYP2D6*10 and tandem duplication of CYP2D6*36-*10 alleles were found at frequencies of 8.7 and 32.7%, respectively. Median dextromethorphan MRs of the subjects carrying CYP2D6*10 and CYP2D6*36-*10 were not significantly different (P = 0.24).

Conclusions

CYP2D6*36 in tandem with CYP2D6*10 plays a minor role in interindividual variation of dextromethorphan metabolism in vivo.

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References

  1. Broly F, Gaedigk A, Heim M, Eichelbaum M, Morike K, Meyer UA (1991) Debrisoquine/sparteine hydroxylation genotype and phenotype: analysis of common mutations and alleles of CYP2D6 in a European population. DNA Cell Biol 10:545–558

    Article  CAS  PubMed  Google Scholar 

  2. Sohn DR, Shin SG, Park CW, Kusaka M, Chiba K, Ishizaki T (1991) Metoprolol oxidation polymorphism in a Korean population: comparison with native Japanese and Chinese populations. Br J Clin Pharmacol 32:504–507

    CAS  PubMed  Google Scholar 

  3. Soyama A, Kubo T, Miyajima A, Saito Y, Shiseki K, Komamura K, Ueno K, Kamakura S, Kitakaze M, Tomoike H, Ozawa S, Sawada J (2004) Novel nonsynonymous single nucleotide polymorphisms in the CYP2D6 gene. Drug Metab Pharmacokinet 19:313–319

    Article  PubMed  Google Scholar 

  4. Matsunaga M, Yamazaki H, Kiyotani K, Iwano S, Saruwatari J, Nakagawa K, Soyama A, Ozawa S, Sawada J, Kashiyama E, Kinoshita M, Kamataki T (2009) Two novel CYP2D6*10 haplotypes as possible causes of a poor metabolic phenotype in Japanese. Drug Metab Dispos 37:699–701

    Article  CAS  PubMed  Google Scholar 

  5. Tateishi T, Chida M, Ariyoshi N, Mizorogi Y, Kamataki T, Kobayashi S (1999) Analysis of the CYP2D6 gene in relation to dextromethorphan O-demethylation capacity in a Japanese population. Clin Pharmacol Ther 65:570–575

    Article  CAS  PubMed  Google Scholar 

  6. Hosono N, Kato M, Kiyotani K, Mushiroda T, Takata S, Sato H, Amitani H, Tsuchiya Y, Yamazaki K, Tsunoda T, Zembutsu H, Nakamura Y, Kubo M (2009) CYP2D6 genotyping for functional-gene dosage analysis by allele copy number detection. Clin Chem 55:1546–1554

    Article  CAS  PubMed  Google Scholar 

  7. Soyama A, Saito Y, Kubo T, Miyajima A, Ohno Y, Komamura K, Ueno K, Kamakura S, Kitakaze M, Tomoike H, Ozawa S, Sawada J (2006) Sequence-based analysis of the CYP2D6*36-CYP2D6*10 tandem-type arrangement, a major CYP2D6*10 haplotype in the Japanese population. Drug Metab Pharmacokinet 21:208–216

    Article  CAS  PubMed  Google Scholar 

  8. Hanioka N, Okumura Y, Saito Y, Hichiya H, Soyama A, Saito K, Ueno K, Sawada J, Narimatsu S (2006) Catalytic roles of CYP2D6.10 and CYP2D6.36 enzymes in mexiletine metabolism: in vitro functional analysis of recombinant proteins expressed in Saccharomyces cerevisiae. Biochem Pharmacol 71:1386–1395

    Article  CAS  PubMed  Google Scholar 

  9. Sakuyama K, Sasaki T, Ujiie S, Obata K, Mizugaki M, Ishikawa M, Hiratsuka M (2008) Functional characterization of 17 CYP2D6 allelic variants (CYP2D6.2, 10, 14A-B, 18, 27, 36, 39, 47-51, 53-55, and 57). Drug Metab Dispos 36:2460–2467

    Article  CAS  PubMed  Google Scholar 

  10. Yamazaki H, Kiyotani K, Tsubuko S, Matsunaga M, Fujieda M, Saito T, Miura J, Kobayashi S, Kamataki T (2003) Two novel haplotype of CYP2D6 gene in a Japanese population. Drug Metab Pharmacokinet 18:269–271

    Article  CAS  PubMed  Google Scholar 

  11. Kiyotani K, Mushiroda T, Imamura CK, Hosono N, Tsunoda T, Kubo M, Tanigawara Y, Flockhart DA, Desta Z, Skaar TC, Aki F, Hirata K, Takatsuka Y, Okazaki M, Ohsumi S, Yamakawa T, Sasa M, Nakamura Y, Zembutsu H (2010) Significant effect of polymorphisms in CYP2D6 and ABCC2 on clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients. J Clin Oncol 28:1287–1293

    Article  CAS  PubMed  Google Scholar 

  12. Johansson I, Oscarson M, Yue QY, Bertilsson L, Sjoqvist F, Ingelman-Sundberg M (1994) Genetic analysis of the Chinese cytochrome P4502D locus: characterization of variant CYP2D6 genes present in subjects with diminished capacity for debrisoquine hydroxylation. Mol Pharmacol 46:452–459

    CAS  PubMed  Google Scholar 

  13. Ramamoorthy Y, Tyndale RF, Sellers EM (2001) Cytochrome P450 2D6.1 and cytochrome P450 2D6.10 differ in catalytic activity for multiple substrates. Pharmacogenetics 11:477–487

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported in part by a Grant-in-Aid from the Ministry of Health, Labour and Welfare of Japan and by SRF in Japan.

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Authors and Affiliations

  1. Laboratory for Pharmacogenetics, RIKEN Center for Medicine, Yokohama, 230-0045, Japan

    Kazuma Kiyotani

  2. Showa Pharmaceutical University, Machida, Tokyo, 194-8543, Japan

    Makiko Shimizu, Tetsuya Kamataki & Hiroshi Yamazaki

  3. St. Marianna University School of Medicine, Kawasaki, Kanagawa, 216-8511, Japan

    Toshio Kumai & Shinichi Kobayashi

  4. Hokkaido University, Sapporo, 060-0812, Japan

    Tetsuya Kamataki

  5. Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, 3-3165 Higashi-tamagawa Gakuen, Machida, Tokyo, 194-8543, Japan

    Hiroshi Yamazaki

Authors
  1. Kazuma Kiyotani
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  2. Makiko Shimizu
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  3. Toshio Kumai
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  4. Tetsuya Kamataki
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  5. Shinichi Kobayashi
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  6. Hiroshi Yamazaki
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Corresponding author

Correspondence to Hiroshi Yamazaki.

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Kiyotani, K., Shimizu, M., Kumai, T. et al. Limited effects of frequent CYP2D6*36-*10 tandem duplication allele on in vivo dextromethorphan metabolism in a Japanese population. Eur J Clin Pharmacol 66, 1065–1068 (2010). https://doi.org/10.1007/s00228-010-0876-4

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  • DOI: https://doi.org/10.1007/s00228-010-0876-4

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