The P450 oxidoreductase genotype is associated with CYP3A activity in vivo as measured by the midazolam phenotyping test.
BACKGROUND
CYP3A4, CYP3A5 and CYP3A7 are hepatic enzymes that metabolize about 50% of drugs on the market, with a large overlap in their specificities. We investigated the genetic bases that contribute to the variation of CYP3A activity.


METHODS
We phenotyped 251 individuals from two independent studies (182 patients treated with methadone and 69 patients with clozapine) for CYP3A activity using the midazolam phenotyping test and genotyped them for CYP3A4, CYP3A5, and CYP3A7 genetic variants, including the single nucleotide polymorphism (SNP) rs4646437C>T in intron 7 of CYP3A4. Owing to the fact that CYP enzymes require electron transfer through the P450 oxidoreductase (POR), and functional impairment has been shown for the POR*28 SNP, this polymorphism was also analysed.


RESULTS
We show that CYP3A4, CYP3A5 and CYP3A7 genotypes, including the SNP rs4646437C>T, do not reflect the inter-individual variability of CYP3A activity (P>0.1). In contrast, POR*28 TT genotype presents a 1.6-fold increase in CYP3A activity compared with POR*28C carriers (n = 182, P = 0.004). This finding was replicated in the second independent dataset (n = 69, P = 0.04).


CONCLUSIONS
The SNP POR*28 seems to be a better genetic marker of the variability of total CYP3A activity in vivo than CYP3A4, CYP3A5 and CYP3A7 genetic variants.
Unit of Biochemistry and Clinical Psychopharmacology, Center for Psychiatric Neurosciences, Department of Psychiatry-CHUV, University of Lausanne, Hospital of Cery, Prilly-Lausanne, Switzerland.
Beatrice
B
Oneda
Severine
S
Crettol
Evelyne
E
Jaquenoud Sirot
Murielle
M
Bochud
Nicolas
N
Ansermot
Chin B
CB
Eap
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003024:Clozapine / Q000097:blood / Q000493:pharmacokinetics; D015331:Cohort Studies; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D008691:Methadone / Q000097:blood / Q000493:pharmacokinetics; D008874:Midazolam / Q000493:pharmacokinetics*; D008875:Middle Aged; D010597:Pharmacogenetics / Q000379:methods*; D010641:Phenotype
D051544:Cytochrome P-450 CYP3A; D003024:Clozapine; D008874:Midazolam; D008691:Methadone