Pharmacogenetic evaluation of ABCB1, Cyp2C9, Cyp2C19 and methylene tetrahydrofolate reductase polymorphisms in teratogenicity of anti-epileptic drugs in women with epilepsy

Abstract

Aim:Pregnancy in women with epilepsy (WWE) who are on anti-epileptic drugs (AEDs) has two- to three-fold increased risk of fetal malformations. AEDs are mostly metabolized by Cyp2C9, Cyp2C19 and Cyp3A4 and transported by ABCB1. Patients on AED therapy can have folate deficiency. We hypothesize that the polymorphisms in ABCB1, Cyp2C9, Cyp2C19 and methylene tetrahydrofolate reductase (MTHFR) might result in differential expression resulting in differential drug transport, drug metabolism and folate metabolism, which in turn may contribute to the teratogenic impact of AEDs.Materials and Methods:The ABCB1, Cyp2C9, Cyp2C19 and MTHFR polymorphisms were genotyped for their role in teratogenic potential and the nature of teratogenecity in response to AED treatment in WWE. The allelic, genotypic associations were tested in 266 WWE comprising of 143 WWE who had given birth to babies with WWE-malformation (WWE-M) and 123 WWE who had normal offsprings (WWE-N).Results:In WWE-M, CC genotype of Ex07 + 139C/T was overrepresented (P = 0.0032) whereas the poor metabolizer allele *2 and *2 *2 genotype of CYP2C219 was significantly higher in comparison to WWE-N group (P = 0.007 and P = 0.005, respectively). All these observations were independent of the nature of malformation (cardiac vs. non cardiac malformations).Conclusion:Our study indicates the possibility that ABCB1 and Cyp2C19 may play a pivotal role in the AED induced teratogenesis, which is independent of nature of malformation. This is one of the first reports indicating the pharmacogenetic role of Cyp2C19 and ABCB1 in teratogenesis of AED in pregnant WWE.

Genetic Susceptibility to Drug Teratogenicity: A Systematic Literature Review

“…Another genetic variant investigated in the AED studies was the rs1805087 variant of MTR in children, which was associated with an increased risk of neurodevelopmental delay and fetal anticonvulsant syndrome in AED-exposed children (Dean et al, 2007 ). The maternal variants CYP2C19 * 2 and rs1202168 of ABCB1 , as well as the haplotype G/C/T (rs2214102/rs1202168/rs1128503) of ABCB1 , were also associated with an increased risk of congenital anomalies upon AED exposure (Jose et al, 2014 ). One study specifically examined the genetic susceptibility to phenytoin teratogenicity and found that a maternal haplotype of EPHX1 C/G (rs1051740/rs2234922) is associated with an increased risk of offspring craniofacial anomalies (Azzato et al, 2010 ).…”

“…The reviewed studies on AEDs mainly investigated MTHFR , which is associated with folate metabolism (Dean et al, 1999 , 2007 ; Kini et al, 2007 ; Jose et al, 2014 ). Folate is essential for both methylation and DNA synthesis, and folate metabolism is important for normal fetal development (Nazki et al, 2014 ).…”

ABCB1 Gene C3435T Polymorphism and Drug Resistance in Epilepsy: Evidence Based on 8604 Subjects

“…After treatment with anti-epileptic drugs (AEDs), most epileptic patients respond well to medications. However, about one-third of newly treated patients do not respond adequately to medications, because these patients exhibit drug resistance to AEDs [ 2 ]. P-glycoprotein (P-gp) was the first discovered human ABC (the ATP-binding cassette) transporter in drug-resistance ovarian cells several decades ago [ 3 ].…”

Data_Sheet_1.docx

“…The reviewed studies on AEDs mainly investigated MTHFR, which is associated with folate metabolism (Dean et al, 1999(Dean et al, , 2007Kini et al, 2007;Jose et al, 2014). Folate is essential for both methylation and DNA synthesis, and folate metabolism is important for normal fetal development (Nazki et al, 2014).…”

“…Another genetic variant investigated in the AED studies was the rs1805087 variant of MTR in children, which was associated with an increased risk of neurodevelopmental delay and fetal anticonvulsant syndrome in AED-exposed children (Dean et al, 2007). The maternal variants CYP2C19 * 2 and rs1202168 of ABCB1, as well as the haplotype G/C/T (rs2214102/rs1202168/rs1128503) of ABCB1, were also associated with an increased risk of congenital anomalies upon AED exposure (Jose et al, 2014). One study specifically examined the genetic susceptibility to phenytoin teratogenicity and found that a maternal haplotype of EPHX1 C/G (rs1051740/rs2234922) is associated with an increased risk of offspring craniofacial anomalies (Azzato et al, 2010).…”