Cited 41 times since 2013 (3.2 per year) source: EuropePMC Pharmacogenomics, Volume 14, Issue 2, 1 1 2013, Pages 137-149 CYP3A4 intron 6 C>T SNP (CYP3A4*22) encodes lower CYP3A4 activity in cancer patients, as measured with probes midazolam and erythromycin. Elens L, Nieuweboer A, Clarke SJ, Charles KA, de Graan AJ, Haufroid V, Mathijssen RH, van Schaik RH
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.
