CYP3A4 Intron 6 C>T SNP (CYP3A4*22) Encodes Lower CYP3A4 Activity in Cancer Patients, as Measured with Probes Midazolam and Erythromycin

Abstract

Aim: The CYP3A4*22 allele was recently reported to be associated with reduced CYP3A4 activity. We investigated the impact of this allele on the metabolism of the CYP3A-phenotyping probes, midazolam (MDZ) and erythromycin. Patients & methods: Genomic DNA from 108 cancer patients receiving intravenous MDZ and 45 undergoing the erythromycin breath test was analyzed for CYP3A4*22 (rs35599367 C>T) and CYP3A5*3. Results: The MDZ metabolic ratio (1´-OH-MDZ:MDZ) was 20.7% (95% CI: -36.2 to -6.2) lower for CYP3A4*22 carriers compared with CYP3A4*1/*1 patients (p = 0.01). Combining CYP3A4*22 and CYP3A5*3 genotypes showed a 38.7% decrease (95% CI: -50.0 to -27.4; p < 0.001) in 1´-OH-MDZ:MDZ for poor (CYP3A4*22–CYP3A5*3/*3) and 28.0% (95% CI: -33.3 to -22.6; p < 0.001) for intermediate (CYP3A4*1/*1–CYP3A5*3/*3) metabolizers, compared with extensive (CYP3A4*1/*1–CYP3A5*1) CYP3A metabolizers. CYP3A4 erythromycin N-demethylation activity was 40% lower in CYP3A4*22 carriers compared with CYP3A4*1/*1 patients (p = 0.032). Conclusion: The CYP3A4*22 allele is associated with decreased CYP3A4-mediated metabolism, as verified by CYP3A-phenotyping probes.

Original submitted 10 September 2012; Revision submitted 3 December 2012

KEYWORDS::

• CYP3A
• CYP3A phenotyping
• CYP3A4*22
• CYP3A5*3
• erythromycin
• midazolam
• pharmacogenetics
• rs35599367
• SNPs

Acknowledgements

The authors would like to thank WJ Loos for his measurements and calculations of the midazolam data.

Financial & competing interests disclosure

L Elens is a postdoctoral researcher with the Fonds National de la Recherche Scientifique, Belgium. 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.