title: 4217C>A polymorphism in carbamoyl-phosphate synthase 1 gene may not associate with hyperammonemia development during valproic acid-based therapy.
abstract: Valproic acid, which is widely used to treat various types of epilepsy, may cause severe hyperammonemia. However, the mechanism responsible for this side effect is not readily apparent. Polymorphisms in the genes encoding carbamoyl-phosphate synthase 1 (CPS1) and N-acetylglutamate synthase (NAGS) were recently reported to be risk factors for the development of hyperammonemia during valproic acid-based therapy. This study aimed to examine the influence of patient characteristics, including polymorphisms in CPS1 4217C>A and NAGS -3064C>A, on the development of hyperammonemia in Japanese pediatric epilepsy patients. The study included 177 pediatric epilepsy patients. The presence of a 4217C>A polymorphism in CPS1 was determined using an allele-specific polymerase chain reaction (PCR)-based method, and the presence of a -3064C>A polymorphism in NAGS was determined using a PCR-based restriction fragment length polymorphism method. Hyperammonemia was defined as a plasma ammonia level exceeding 200 μg/dL. We observed a significant difference between the combination of valproic acid with phenytoin and the development of hyperammonemia in both univariate and multivariate analyses. With regard to the CPS1 4217C>A polymorphism, we did not observe a significant association with the development of hyperammonemia. In conclusion, CPS1 4217C>A polymorphism may not be associated with the development of hyperammonemia in Japanese population.
authors.affiliation: Department of Clinical Pharmacology & Genetics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka City, Shizuoka 422-8526, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Inoue
authors.affiliation: Department of Clinical Pharmacology & Genetics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka City, Shizuoka 422-8526, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Suzuki
authors.affiliation: Department of Clinical Pharmacology & Genetics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka City, Shizuoka 422-8526, Japan.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Department of Clinical Research, National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, 886 Urushiyama, Aoi-ku, Shizuoka City, Shizuoka 420-8688, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Department of Clinical Pharmacology & Genetics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka City, Shizuoka 422-8526, Japan.
authors.forename: Rei
authors.initials: R
authors.lastname: Yazawa
authors.affiliation: Department of Clinical Research, National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, 886 Urushiyama, Aoi-ku, Shizuoka City, Shizuoka 420-8688, Japan.
authors.forename: Yukitoshi
authors.initials: Y
authors.lastname: Takahashi
authors.affiliation: Department of Clinical Research, National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, 886 Urushiyama, Aoi-ku, Shizuoka City, Shizuoka 420-8688, Japan.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Imai
authors.affiliation: Department of Clinical Research, National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, 886 Urushiyama, Aoi-ku, Shizuoka City, Shizuoka 420-8688, Japan.
authors.forename: Kou
authors.initials: K
authors.lastname: Miyakawa
authors.affiliation: Department of Clinical Research, National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, 886 Urushiyama, Aoi-ku, Shizuoka City, Shizuoka 420-8688, Japan.
authors.forename: Yushi
authors.initials: Y
authors.lastname: Inoue
authors.affiliation: Department of Clinical Pharmacology & Genetics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka City, Shizuoka 422-8526, Japan.
authors.forename: Daiki
authors.initials: D
authors.lastname: Tsuji
authors.affiliation: Department of Clinical Pharmacology & Genetics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka City, Shizuoka 422-8526, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Hayashi
authors.affiliation: Department of Clinical Pharmacology & Genetics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka City, Shizuoka 422-8526, Japan. Electronic address: itohk@u-shizuoka-ken.ac.jp.
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Itoh
mesh_terms: D000483:Alleles; D051046:Amino-Acid N-Acetyltransferase / Q000235:genetics; D000641:Ammonia / Q000097:blood; D000927:Anticonvulsants / Q000009:adverse effects* / Q000097:blood / Q000627:therapeutic use; D044466:Asian People / Q000235:genetics; D054316:Biomarkers, Pharmacological; D002222:Carbamoyl-Phosphate Synthase (Ammonia) / Q000235:genetics*; D002648:Child; D004827:Epilepsy / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D022124:Hyperammonemia / Q000097:blood / Q000139:chemically induced* / Q000235:genetics*; D007564:Japan; D008297:Male; D010672:Phenytoin / Q000009:adverse effects / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D014635:Valproic Acid / Q000009:adverse effects* / Q000097:blood / Q000627:therapeutic use
chemical_list: D000927:Anticonvulsants; D054316:Biomarkers, Pharmacological; D014635:Valproic Acid; D010672:Phenytoin; D000641:Ammonia; D051046:Amino-Acid N-Acetyltransferase; C494874:NAGS protein, human; D002222:Carbamoyl-Phosphate Synthase (Ammonia)
keywords: Carbamoyl-phosphate synthase 1; Epilepsy; Hyperammonemia; N-Acetylglutamate synthase; Valproic acid