Genetic polymorphisms of CYP1A2, CYP3A4, CYP3A5, pregnane/steroid X receptor and constitutive androstane receptor in 207 healthy Spanish volunteers.
BACKGROUND
Variability of cytochrome P450 (CYP) in humans is largely related to the pharmacological and toxicological effects of drugs and chemicals. Identification of single nucleotide polymorphisms (SNPs) could be important for knowing their involvement in many drugs metabolism. The goal of this study was to analyze the genotype frequency of 10 SNPs related to mirtazapine metabolism [CYP3A4*17, CYP3A4*18, CYP3A5*3A, CYP1A2*1F, pregnane/steroid X receptor (PXR) (rs3814055, rs38114057, rs3814058) and constitutive androstane receptor (CAR) (rs4073054, rs2307424, rs2502815)].


METHODS
The study was carried out in 207 healthy Spanish volunteers that had participated in phase I clinical trials. Other studies were performed: Hardy-Weinberg equilibrium, haplotype estimation and linkage disequilibrium.


RESULTS
No mutation related to CYP3A4*17 and CYP3A4*18 was found. Therefore, we analyzed data for the other eight SNPs. Allele frequencies were in equilibrium with the Hardy-Weinberg equation. Six haplotypes were determined for three PXR SNPs, and four for CAR SNPs. Tests for linkage disequilibrium showed a high association between PXR (rs38114057) and PXR (rs3814058) (p= 0.001), and between the three CAR SNPs (p=0.001), which could be useful for identification of tag SNPs.


CONCLUSIONS
In the present study, the genotype frequencies of some SNPs related to mirtazapine metabolism in Spaniards were analyzed and showed that our study population is representative of HapMap European population. The results obtained could be analyzed with pharmacokinetic parameters of mirtazapine to elucidate the genotype-phenotype relationship, the involvement of these SNPs in metabolic reactions, drug interactions, and prediction of treatment response.
Oliver
Paloma
P
Department of Clinical Pathology, La Paz University Hospital, Madrid, Spain. poliver.hulp@salud.madrid.org
Lubomirov
Rubin
R
Carcas
Antonio
A
D000328:Adult; D000090702:Constitutive Androstane Receptor; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear / Q000145:classification / Q000235:genetics*; D011987:Receptors, Steroid / Q000145:classification / Q000235:genetics*; D013030:Spain; D044465:White People / Q000235:genetics*; D055815:Young Adult
D000090702:Constitutive Androstane Receptor; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; C504573:CYP1A2 protein, human; C510164:CYP3A5 protein, human; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human