Pharmacogenetics of immunosuppressant polymorphism of CYP3A5 in renal transplant recipients.
The tacrolimus is metabolized primarily by CYP3A5, a member of the single nucleotide polymorphism family. It shows cytochrome P450 (SNP) in intron 3, which consists of a change of base, G for A, producing a stop codon. The result is a nonfunctional protein (allele *3). Allele *1 is the wild type. The patients that show the allelic variant *3 in homozygosis (G/G) are slow metabolizers of the immunosuppressant, increasing its concentration in blood. In contrast, heterozygote A/G alleles *1/*3 are intermediate metabolizers, whereas those of allele *1 in homozygosis (A/A) are normal metabolizers. The aim of this study was to determine CYP 3A5 polymorphism among adult renal transplant recipients and the general Argentinean population. We analyzed 21 recipients and 36 healthy controls. All subjects gave written informed consent approved by the local committee. To determine the polymorphism, we extracted DNA from peripheral blood and used polymerase chain reaction (PCR) to amplify intron 3 of the CYP 3A5. The presence of variant was confirmed by direct sequencing. Among the controls the CYP3A5 genotype *3/*3 (G/G) was detected in 32 individuals, 4 showed *1/*3 (A/G), and none had *1/*1 (A/A); among the recipients, the results were as follows: 18, 2, and 1, respectively. The frequencies of polymorphism in both groups were similar, although they differed from those published for other populations. These results are the basis for the development of a pharmacogenomic program applied to organ transplantation. The genetic polymorphisms can determine responses to drugs. The molecular diagnosis must be transferred to clinical practice so as to guide selection of medicine and drug doses to be optimal for each individual.
Larriba
J
J
Instituto de Ciencias Básicas y Medicina Experimental, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina.
Imperiali
N
N
Groppa
R
R
Giordani
C
C
Algranatti
S
S
Redal
M A
MA
D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000097:blood / Q000235:genetics / Q000302:isolation & purification; D017931:DNA Primers; D005787:Gene Frequency; D006580:Genetic Carrier Screening; D005838:Genotype; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000276:immunology*; D016133:Polymerase Chain Reaction / Q000379:methods; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D016559:Tacrolimus / Q000378:metabolism / Q000627:therapeutic use
D017931:DNA Primers; D007166:Immunosuppressive Agents; D004247:DNA; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus