title: CYP3A4 intron 6 C>T SNP (CYP3A4*22) encodes lower CYP3A4 activity in cancer patients, as measured with probes midazolam and erythromycin.
abstract: OBJECTIVE
  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.
  
  
  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).
  
  
  CONCLUSIONS
  The CYP3A4*22 allele is associated with decreased CYP3A4-mediated metabolism, as verified by CYP3A-phenotyping probes.
authors: Department of Clinical Chemistry, Erasmus University Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
authors: Laure
authors: L
authors: Elens
authors: Annemieke
authors: A
authors: Nieuweboer
authors: Stephen J
authors: SJ
authors: Clarke
authors: Kellie A
authors: KA
authors: Charles
authors: Anne-Joy
authors: AJ
authors: de Graan
authors: Vincent
authors: V
authors: Haufroid
authors: Ron H J
authors: RH
authors: Mathijssen
authors: Ron H N
authors: RH
authors: van Schaik
mesh_terms: D001944:Breath Tests; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism*; D004247:DNA / Q000235:genetics; D004917:Erythromycin / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D007438:Introns / Q000235:genetics; D008297:Male; D008657:Metabolic Clearance Rate; D008874:Midazolam / Q000097:blood / Q000493:pharmacokinetics*; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000201:enzymology*; D020641:Polymorphism, Single Nucleotide
chemical_list: D004917:Erythromycin; D004247:DNA; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam