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Phenotype-genotype analysis of CYP1A2 in Japanese patients receiving oral theophylline therapy

  • Pharmacogenetics
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Objective

To clarify the association between the cytochrome P450 (CYP) 1A2 genotype with the CYP1A2 phenotype and to search for the CYP1A2*1K haplotype, which has been shown to decrease CYP1A2 inducibility and/or other functional polymorphisms in Japanese.

Methods

Two polymorphisms, CYP1A2*1C and CYP1A2*1F, were genotyped in 126 patients receiving oral slow-release theophylline (TP) therapy and in 224 healthy volunteers. The CYP1A2 phenotype was assessed by the plasma [1-methyluric acid (1U) + 3-methylxanthine (3X)]/TP ratio in the patients. The volunteers were given 150 mg caffeine, and the urine [1X+1U+5-acetylamino-6-amino-3-methyluracil (AAMU)]/17U ratio was used for CYP1A2 phenotyping. CYP1A2 intron 1 and six exons (exon 2-exon 7) were sequenced in the patients whose (1U+3X)/TP ratios were below the mean−2SD of those of all patients, and intron 1 was also sequenced in an additional 20 healthy volunteers exhibiting putative low CYP1A2 activities.

Results

The individual (1U+3X)/TP ratios ranged from 0.007 to 0.21 (a 30-fold difference) in the patients, and the (1X+1U+AAMU)/17U ratios ranged from 1.6 to 112 (a 70-fold difference) in the healthy volunteers. The CYP1A2 activities were not significantly influenced by CYP1A2*1C or CYP1A2*1F. We found no functional polymorphisms by a sequencing analysis.

Conclusion

These results suggest that the CYP1A2*1C and CYP1A2*1F genotypes are not crucial factors for the variability of CYP1A2 activity and that the CYP1A2*1K haplotype is either nil or only shows a very low frequency in Japanese.

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Acknowledgements

This work was supported by a grant–in–aid (no. 16590438–0) for scientific research from the Japanese Ministry of Education, Science, Sports and Culture, and by a grant–in–aid (no. 99–2) from the Organization for Pharmaceutical Safety and Research (OPSR), Tokyo, Japan. We gratefully thank Takashi Hagiwara, Kanako Johno, and Tomonobu Shiraishi for their contribution, as well as the staff of Kumamoto City Hospital and Japanese Red Cross Kumamoto Health Care Center for their clinical support. This study complies with the current laws of Japan, where it was performed inclusive of ethics approval.

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Authors and Affiliations

  1. Division of Pharmacology and Therapeutics, Graduate School of Medical and Pharmaceutical Science, Kumamoto University, Oe-honmachi 5-1, Kumamoto, 862-0973, Japan

    Keiji Takata, Junji Saruwatari, Naoyuki Nakada, Mizuna Nakagawa & Kazuko Nakagawa

  2. Department of Medicine, Kumamoto City Hospital, Kumamoto, Japan

    Koichiro Fukuda & Shinobu Takenaka

  3. Department of Medicine, Omotesando Yoshida Hospital, Kumamoto, Japan

    Fujiho Tanaka

  4. Japanese Red Cross Kumamoto Health Care Center, Kumamoto, Japan

    Shuichi Mihara & Toru Marubayashi

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  1. Keiji Takata
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  2. Junji Saruwatari
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  3. Naoyuki Nakada
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  4. Mizuna Nakagawa
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  5. Koichiro Fukuda
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  7. Shinobu Takenaka
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  10. Kazuko Nakagawa
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Correspondence to Kazuko Nakagawa.

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Takata, K., Saruwatari, J., Nakada, N. et al. Phenotype-genotype analysis of CYP1A2 in Japanese patients receiving oral theophylline therapy. Eur J Clin Pharmacol 62, 23–28 (2006). https://doi.org/10.1007/s00228-005-0057-z

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  • DOI: https://doi.org/10.1007/s00228-005-0057-z

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