Preventive Effect of Vitamin B6 on Developmental Toxicity of Carbamazepine in Mice

Document Type : Original Article

Authors

1 Department of Anatomy, Birjand University of Medical Sciences, Birjand, Iran

2 Pharmaceutical Sciences Research Center, Medical Toxicology Research Center, Department of Pharmacodynamics and Toxicology, Mashhad University of Medical Sciences, Mashhad, Iran

3 Department of Biology, Azad Islamic University of Mashhad, Mashhad, Iran

4 Gorgan Congenital Malformations Center, Golestan University of Medical Sciences, Gorgan, Iran

Abstract

Objective(s)
Carbamazepine (CBZ) is an antiepileptic drug that is used widely for the treatment of epileptic seizures. Neural tube defects (NTDs), growth retardation, and nail hypoplasia are the most common features of teratogenic effects of this drug. The purpose of this study was to examine the effect of vitamin B6 on the developmental toxicity of CBZ on mice.
Materials and Methods
Sixty BALB/c pregnant mice were divided into four experimental and two control groups. Two experimental groups received daily intraperitoneal injection (IP) of 30 mg/kg (I) or 60 mg/kg (II) of CBZ on gestational days (GD) 6 to 15. Two other experimental groups received daily IP injection of 30 mg/kg (III) or 60 mg/kg (IV) of CBZ with 10 mg/kg/day vitamin B6 by gavage 10 days prior to gestation and on GD 6 to 15. Two control groups received normal saline or Tween 20. Dams underwent Cesarean section on GD 18 and embryos were harvested. External/macroscopic observation of fetuses was done by stereomicroscope and external examination for malformations was recorded. Data analyzed by ANOVA and X2 test using SPSS software.
Results
The mean weight and crown-rump of the fetuses in both CBZ-treated experimental groups were significantly reduced compared with those of the control groups. Various malformations were detected such as brachygnathia, eye malformations, NTDs, vertebral deformity, brachydactyly and growth retardation. Vitamin B6 treatment significantly reduced various CBZ-induced malformations.
Conclusion
This study showed that vitamin B6 has a preventive effect on the developmental toxicity of CBZ in mice that can be pursued further for clinical research.

Keywords

References

1. Ornoy A. Neuroteratogens in man: an overview with special emphasis on the teratogenicity of antiepileptic drugs in pregnancy. Reprod Toxicol 2006; 22:214-226.
2. Hiremath GK, Kotagal P, Bingaman W, Hovinga C, Wyllie E, Morris H, et al., Risk factors for carbamazepine elevation and toxicity following epilepsy surgery. Seizure 2005; 14:312-317.
3. Perez Martin JM, Fernández Freire P, Labrador V, Hazen MJ. Carbamazepine induces mitotic arrest in
mammalian Vero cells. Mutat Res 2008; 637:124-133.
4. Christensen HD, Rayburn WF, Parker KM, Gonzalez CL, Gold KP. Chronic prenatal exposure to carbamazepine and perinatal outcomes of C3H/He mice. Am J Obstet Gynecol 2004; 190:259-263.
5. Matalon S, Schechtman S, Goldzweig G, Ornoy A. The teratogenic effect of carbamazepine: a meta-analysis of 1255 exposures. Reprod Toxicol 2002; 16: 9-17.
6. Lindhout D, Hoppener RJ, Meinardi H. Teratogenicity of antiepileptic drug combinations with special emphasis on epoxidation (of carbamazepine). Epilepsia 1984; 25:77-83.
7. Tomson T, Battino D. Teratogenic effects of antiepileptic drugs. Seizure 2008; 17:166-171.
8. Artama M, Ritvanen A, Gissler M, Isojärvi J, Auvinen A. Congenital structural anomalies in offspring of women with epilepsy--a population-based cohort study in Finland. Int J Epidemiol 2006; 35:280-287.
9. Biale Y, Lewenthal H. Effect of folic acid supplementation on congenital malformations due to anticonvulsive drugs. Eur J Obstet Gynecol Reprod Biol 1984; 18:211-216.
10. Afshar M, Moallem SA, Houshang Mohammadpour A, Shiravi A, Majid Jalalian S, Jafar Golalipour M. Teratogenic effects of carbamazepine on embryonic eye development in pregnant mice. Cutan Ocul Toxicol 2010; 29:10-15.
11. Sutcliffe AG, Jones RB, Woodruff G. Eye malformations associated with treatment with carbamazepine during pregnancy. Ophthalmic Genet 1998; 19:59-62.
12. Kannan K, Jain SK. Effect of vitamin B6 on oxygen radicals, mitochondrial membrane potential, and lipid peroxidation in H2O2-treated U937 monocytes. Free Radic Biol Med 2004; 36:423-428.
13. Sener U, Zorlu Y, Karaguzel O, Ozdamar O, Coker I, Topbas M.Effects of common anti-epileptic drug monotherapy on serum levels of homocysteine, vitamin B12, folic acid and vitamin B6. Seizure 2006; 15:79-85.
14. Tamura T, Aiso K, Johnston KE, Black L, Faught E. Homocysteine, folate, vitamin B-12 and vitamin B-6 in patients receiving antiepileptic drug monotherapy. Epilepsy Res 2000; 40:7-15.
15. Perna AF, Ingrosso D, Lombardi C, Acanfora F, Satta E, Cesare CM, Violetti E, et al. Possible mechanisms of  homocysteine toxicity. Kidney Int Suppl 2003: S137-140.
16. Azarbayjani F, Danielsson BR. Pharmacologically induced embryonic dysrhythmia and episodes of hypoxia followed by reoxygenation: a common teratogenic mechanism for antiepileptic drugs. Teratology 1998; 57:117-126.
17. Diav-Citrin O, Shechtman S, Arnon J, Ornoy A. Is carbamazepine teratogenic? A prospective controlled study of 210 pregnancies. Neurology 2001; 57:321-324.
18. Jones KL, Lacro RV, Johnson KA, Adams J. Pattern of malformations in the children of women treated with carbamazepine during pregnancy. N Engl J Med 1989; 320:1661-1666.
19. Vorhees CV, Acuff KD, Weisenburger WP, Minck DR. Teratogenicity of carbamazepine in rats. Teratology 1990; 41:311-317.
20. Lumeng L, Cleary RE, Wagner R, Yu P-L, Li T-K. Adequacy of vitamin B6 supplementation during pregnancy: a prospective study. Am J Clin Nutr 1976; 29: 1376-1383.
21. Schuster K,Bailey LB, Mahan CS. Vitamin B6 status of low-income adolescent and adult pregnant women and the condition of their infants at birth. Am J Clin Nutr 1981; 34:1731-175.
22. Leeda M, Riyazi N, de Vries JI, Jakobs C, van Geijn HP, Dekker GA. Effects of folic acid and vitamin B6 supplementation on women with hyperhomocysteinemia and a history of preeclampsia or fetal growth restriction. Am J Obstet Gynecol 1998; 179: 135-139.
23. Schubert J, Schmidt F, Syska E. B group vitamins and cleft lip and cleft palate. Int J Oral Maxillofac Surg 2002; 31:410-413.
24. Piersma AH, Verhoef A, Opperhuizen A, Klaassen R, van Eijkeren J, Olling M. Embryotoxicity of carbamazepine in rat postimplantation embryo culture after in vitro exposure via three different routes. Reprod Toxicol 1998; 12:161-168.
25. Williams CP, Marsh CS, Hodgkins PR. Persistent fetal vasculature associated with orbital lymphangioma. J Aapos 2006; 10:285-286.
26. Kroes HY, Reefhuis J. Natural history of homocystinuria due to cystathionine beta-synthase deficiency. Am J Hum Genet 1985; 37:1-31.
27. Mudd SH, Skovby F, Levy HL, Pettigrew KD, Wilcken B, Pyeritz RE, et al. The natural history of homocystinuria due to cystathionine beta-synthase deficiency. Am J Hum Genet 1985; 37:1-31.
28. Holmes LB. The teratogenicity of anticonvulsant drugs: a progress report. J Med Genet 2002; 39:245 247.
29. Candito M, Gueant JL, Naimi M, Bongain A, Van Obberghen E. Antiepileptic drugs: a case report in a pregnancy with a neural tube defect. Pediatr Neurol. 2006; 34:323-324.
30. Wide K, Winbladh B, Kallen B. Major malformations in infants exposed to antiepileptic drugs in ut ero, with emphasis on carbamazepine and valproic acid: a nation-wide, population-based register study. Acta Paediatr 2004; 93:174-176.
31. Van Rooij IA, Swinkels DW, Blom HJ, Merkus HM, Steegers-Theunissen RP. Vitamin and homocysteine status of mothers and infants and the risk of nonsyndromic orofacial clefts. Am J Obstet Gynecol 2003; 189:1155-1160.
32. Wong WY, Eskes TK, Kuijpers-Jagtman AM, Spauwen PH, Steegers EA, Thomas CM, et al. Nonsyndromic orofacial clefts: association with maternal hyperhomocysteinemia. Teratology 1999; 60:253-257.
33. Fritz H, Muller D, Hess R. Comparative study of the teratogenicity of phenobarbitone, diphenylhydantoin and carbamazepine in mice. Toxicology 1976; 6:323-330.
34. Ornoy A, Cohen E. Outcome of children born to epileptic mothers treated with carbamazepine during pregnancy. Arch Dis Child 1996; 75:517-520.
35. Apeland T, Froyland ES, Kristensen O, Strandjord RE, Mansoor MA. Drug-induced pertubation of the aminothiol redox-status in patients with epilepsy: improvement by B-vitamins. Epilepsy Res 2008; 82:1-6.
36. Azarbayjani F, Danielsson BR. Embryonic arrhythmia by inhibition of HERG channels: a common hypoxiarelated teratogenic mechanism for antiepileptic drugs? Epilepsia 2002; 43:457-468.
37. Hamelet J, Seltzer V, Petit E, Noll C, Andreau K, Delabar JM, et al. Cystathionine beta synthase deficiency induces catalase-mediated hydrogen peroxide detoxification in mice liver. Biochim Biophys Acta 2008; 1782:482-488.

Files

Share

How to cite

Statistics