Association of ABCB1, CYP3A4, EPHX1, FAS, SCN1A, MICA,and BAG6 polymorphisms with the risk of carbamazepine‐induced Stevens‐Johnson syndrome/toxic epidermal necrolysis in Chinese Han patients with epilepsy

Abstract

SUMMARYObjective: This study explored the association between the risk of carbamazepine (CBZ)-induced Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) and CBZ dose, dose-adjusted concentration, and ABCB1, CYP3A4, EPHX1, FAS, SCN1A, MICA, and BAG6 polymorphisms in patients of Han ethnicity with epilepsy who were living in northeastern China. Materials and methods: We determined the genotypes of patients with CBZ-SJS/TEN and CBZ-tolerant patients, who were used as controls, for ABCB1, CYP3A4, EPHX1, FAS, SCN1A, MICA, and BAG6 polymorphisms by polymerase chain reaction (PCR) amplification and direct sequencing. We measured the steady-state serum CBZ concentrations using fluorescence polarization immunoassay for the control patients. Results: We observed statistically significant differences in EPHX1 c.337T>C polymorphisms between patients with CBZ-SJS/TEN and CBZ-tolerant controls in terms of allelic and genotypic frequencies (p = 0.011 and p = 0.007, respectively). The C allele and the C-G diplotype of EPHX1 may play important roles in increasing the risk of CBZ-SJS/TEN development (odds ratio [OR] 0.478, 95% confidence interval [CI] = 0.267-0.855, p = 0.011; OR = 0.213, 95% CI = 0.049-0.930, p = 0.025, respectively). We did not observe any significant associations between ABCB1, CYP3A4, EPHX1, FAS, SCN1A, MICA or BAG6 genes and CBZ dose or dose-adjusted concentration in CBZ-tolerant patients. Significance: We found a significant association between EPHX1 c.337T>C polymorphisms and the development of CBZ-SJS/TEN in patients of Han ethnicity living in northeastern China. EPHX1 c.337T>C polymorphisms may contribute to the risk of severe CBZ-SJS/TEN by increasing the concentration of a CBZ metabolite, CBZ-10,11-epoxide, in patients with epilepsy. KEY WORDS: carbamazepine, SJS/TEN, EPHX1.Carbamazepine (CBZ) is a first-line choice for drug monotherapy for the treatment of partial and generalized tonic-clonic seizures, and it is the most commonly prescribed antiepileptic drug (AED) for adult-onset seizure disorders in the developed world. However, CBZ is associated with hypersensitivity reactions that range from benign urticaria to life-threatening cutaneous disorders, such as Stevens-Johnson syndrome (SJS) and the related disease toxic epidermal necrolysis (TEN). The mortality rate of SJS/TEN is nearly 30%. In 2004, a strong association was

Carbamazepine-Mediated Adverse Drug Reactions: CBZ-10,11-epoxide but Not Carbamazepine Induces the Alteration of Peptides Presented by HLA-B∗15:02

“…In Caucasians, the allele A∗31:01 is associated with CBZ-mediated ADRs, since B∗15:02 is not prevalent in this population [ 52 ]; thus, these results do not play a role in B∗15:02-associated CBZ hypersensitivity in Han Chinese population. Another study analyzed the association of polymorphisms in the multidrug resistance protein 1 (ABCB1), CYP3A4, EPHX1, FAS, and SCN1a in Han Chinese, where the allele B∗15:02 is common [ 63 ]. An increased risk of CBZ-mediated SJS/TEN in patients carrying the EPHX1 c.337T>C polymorphism was found.…”

“…Therefore, we hypothesize that not metabolization of CBZ to EPX but mainly further detoxification of EPX plays a role in B∗15:02-associated CBZ hypersensitivity. A higher level of EPX might have a bigger influence than the initial dose of CBZ, since the occurrence of an ADR was independent of the CBZ dosage [ 63 ]. Modified metabolization of EPX might facilitate alterations in peptide presentation according to the altered repertoire model with EPX binding to the PBR in the F pocket.…”

“…Thus far, it is unclear whether CBZ, EPX, or both substances are contributing to HLA-associated hypersensitivity reactions. Interestingly, He et al [ 63 ] showed an increasing risk of SJS/TEN that is dependent on the epoxide hydrolase 1 (EPHX1) polymorphism, yet no influence of CYP3A4, multidrug resistance protein 1, FAS, and SCN1a polymorphism in Chinese Han population could be observed.…”

Valproate-Induced Reversible Brain Atrophy and Cognitive Deterioration

“…Current studies find that the HLA-DRB1*15.01 allele is a risk factor for AED-induced SJS/TEN among Han Chinese, whereas HLA-A*33.03, HLA-B*58.01, and HLA-DRB1*03.01 alleles may be protectors against AED-induced skin reactions, especially CBZ-SJS/TEN [6]. Patients of Han ethnicity living in northeastern China and having EPHX1 c.337T>C polymorphisms also show an increased risk of developing CBZ-SJS/TEN, related to an increased concentration of a CBZ metabolite, CBZ-10,11-epoxide [7]. The discovery of a functional link of genetic variants to the phenytoin, carbamazepine, and other aromatic AED-related hypersensitivity cutaneous reactions might lead to prospective preventive genetic testing.…”

The relationship between pharmacokinetic parameters of carbamazepine and therapeutic response in epileptic patients

“…The metabolite is fully converted by epoxide-hydrolase (EPHX1) to carbamazepine-10,11-diol, which is excreted in the urine in a free or a conjugated form [ 11 ]. These enzymes may constitute modulating factors of metabolic profiles of CBZ and can be implicated in the control of the therapeutic efficacy and toxicity of the CBZ [ 12 – 15 ].…”