Association Analysis of CYP2A6 Genotypes and Haplotypes with 5-Fluorouracil Formation from Tegafur in Human Liver Microsomes

Abstract

Aim: Tegafur is primarily converted to 5-fluorouracil (5-FU) by CYP2A6 in the human liver to exert its antitumor effect. Our objective was to comprehensively investigate the effects of CYP2A6 genetic polymorphisms on tegafur bioactivation activity. Materials & methods: Using a set of over 45 Chinese livers, the association between CYP2A6 genetic variations and 5-FU formation rates from tegafur, as well as CYP2A6 mRNA and protein levels, was determined. Results: A total of 20 polymorphic variants and 20 haplotypes of CYP2A6 were identified. From genotype/haplotype–phenotype association tests, we demonstrated that CYP2A6*4 was the main allele responsible for the decreased 5-FU formation from tegafur and CYP2A6 expression in this population. By contrast, haplotype 14 (a novel CYP2A6*1B allele) was associated with increased microsomal 5-FU formation activity and CYP2A6 expression, and this may be attributed to the combined effects of three single variants (g.22C>T, g.1620T>C and a gene conversion in the 3´-UTR) included in this haplotype. Conclusion: We concluded that CYP2A6*4 and the novel CYP2A6*1B variant were the major genetic determinants of interindividual variability in 5-FU formation from tegafur in Chinese livers.

Original submitted 2 November 2010; Revision submitted 3 December 2010.

KEYWORDS::

• 5-fluorouracil
• Chinese
• CYP2A6
• genetic polymorphism
• haplotype
• tegafur

Acknowledgements

The authors thank Jin Yang for his valuable advice and Melanie Webster for her critical reading of the manuscript.

Financial & competing interests disclosure

This work was supported by the National High-Tech Research and Development Program of China (863 Program; Grant 2009AA022710). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

This work was supported by the National High-Tech Research and Development Program of China (863 Program; Grant 2009AA022710). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.