The Absence of CYP3A5*3 Is a Protective Factor to Anticonvulsants Hypersensitivity Reactions: A Case-Control Study in Brazilian Subjects.
Although aromatic anticonvulsants are usually well tolerated, they can cause cutaneous adverse drug reactions in up to 10% of patients. The clinical manifestations of the antiepileptics-induced hypersensitivity reactions (AHR) vary from mild skin rashes to severe cutaneous drug adverse reactions which are related to high mortality and significant morbidity. Genetic polymorphisms in cytochrome P450 genes are associated with altered enzymatic activity and may contribute to the risk of AHR. Here we present a case-control study in which we genotyped SNPs of CYP2C19, 2C9 and 3A5 of 55 individuals with varying severities of AHR, 83 tolerant, and 366 healthy control subjects from São Paulo, Brazil. Clinical characterization was based on standardized scoring systems and drug patch test. All in vivo investigation followed the ENDA (European Network of Drug Allergy) recommendations. Genotype was determined by real time PCR using peripheral blood DNA as a template. Of all 504 subjects, 65% were females, 45% self-identified as Afro-American, 38% as Caucasian and 17% as having non-African mixed ascendancy. Amongst 55 subjects with AHR, 44 had severe cutaneous drug adverse reactions. Of the 46 drug patch tests performed, 29 (63%) were positive. We found a strong association between the absence of CYP3A5*3 and tolerant subjects when compared to AHR (p = 0.0002, OR = 5.28 [CI95% 2.09-14.84]). None of our groups presented positive association with CYP2C19 and 2C9 polymorphisms, however, both SNPs contributed to separation of cases and tolerants in a Classification and Regression Tree. Our findings indicate that drug metabolism genes can contribute in the tolerability of antiepileptics. CYP3A5*3 is the most prevalent CYP3A5 allele associated with reduced enzymatic function. The current study provides evidence that normal CYP3A5 activity might be a protective factor to aromatic antiepileptics-induced hypersensitivity reactions in Brazilian subjects.
Clinical Immunology and Allergy Division, University of São Paulo, São Paulo, Brazil.
Luciana Kase
LK
Tanno
Laboratory of Neuroscience - LIM-27 Institute of Psychiatry, University of São Paulo, São Paulo, Brazil; Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, São Paulo, Brazil.
Daniel Shikanai
DS
Kerr
Nursing School of the University of São Paulo, São Paulo, Brazil.
Bernardo
B
dos Santos
Laboratory of Neuroscience - LIM-27 Institute of Psychiatry, University of São Paulo, São Paulo, Brazil; Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, São Paulo, Brazil.
Leda Leme
LL
Talib
Laboratory of Immunology - LIM-19 Clinical Immunology and Allergy Division, University of São Paulo, São Paulo, Brazil.
Célia
C
Yamaguti
Laboratory of Immunology - LIM-19 Clinical Immunology and Allergy Division, University of São Paulo, São Paulo, Brazil.
Helcio
H
Rodrigues
Laboratory of Neuroscience - LIM-27 Institute of Psychiatry, University of São Paulo, São Paulo, Brazil; Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, São Paulo, Brazil.
Wagner Farid
WF
Gattaz
Clinical Immunology and Allergy Division, University of São Paulo, São Paulo, Brazil; Laboratory of Immunology - LIM-19 Clinical Immunology and Allergy Division, University of São Paulo, São Paulo, Brazil.
Jorge
J
Kalil
D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000009:adverse effects*; D001938:Brazil / Q000453:epidemiology; D016022:Case-Control Studies; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D004342:Drug Hypersensitivity / Q000453:epidemiology* / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
D000927:Anticonvulsants; D065729:Cytochrome P-450 CYP2C9; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A