Pamukçu Özlem BARAN, Ayşe YILDIRIM, Murat AKKUŞ

The protective role of folic acid and vitamin E against toxical effects of valproic acid on liver tissue during period of gestation

Valproik asit epilepside kullanılan antikonvülzan bir ilaçtır. Valproik Asit’in karaciğer üzerinde yaptığı histopatolojik değişiklikler ile folik asit ve vitamin E’nin koruyucu etkileri incelendi. 24 erişkin dişi Wistar Albino tipi sıçan kullanıldı. Birinci grup kontrol, ikinci grup gebeliğin 8.9. ve 10. günlerinde 300mg/kg dozunda valproik asit verilen grup, üçüncü grup valproik asit+vitamin E grubuydu. Vitamin E, valproik asit uygulamasından bir saat önce 250mg/kg dozunda nazogastrik intübasyonla yine gebeliğin 8.9.10.günlerinde verildi. Dördüncü valproik asit+folik asit grubuna valproik asit yanında, içme suyuna düzenli olarak her gün 400 mikrogram dozunda folik asit katıldı. Valproik asit grubunun karaciğer kesitlerinde perivenüller dilatasyon, Kuppfer hücre şişmesi, mikroveziküler steatozis ve dejenerasyon izlendi. Üçüncü grubun hepatositlerinde orta derecede dejenerasyon, bazı yerlerde nekrotik alanlar ve mononükleer hücre infiltrasyonu görüldü. Dördüncü grupta Remark hücre kordonlarının görünümü normale yakındı. Bu bulguların ışığı altında folik asit ve vitamin E kullanarak antioksidanların hepatotoksisiteyi azalttığını izledik.

Anahtar Kelimeler:

Folik asit, Karaciğer, Gebelik, Valproik asit, Sıçan, Wistar, Vitamin E

Gebelik sürecinde valproik asitin karaciğer dokusundaki toksik etkilerine karşı folik asit ve vitamin E'nin koruyucu rolü

Valproic acid is an anticonvulsan drug used in epilepsy. The histopathological changes of valproic acid on liver and the protective effect of vitamin E and also folic acid were observed. 24 adult female Wistar Albino rats were used. The first control, the second valproic acid group that was given 300 mg/kg on 8.9. and 10. days of gestation, the third valproic acid +vitamin E group. Vitamin E was given 250mg/kg via nasogastric intubation before one hour administration of valproic acid on 8.9.10.days of gestation. The fourth valproic acid+ folic acid group; via valproic acid, folic acid was given 400 microgram ordinarily in drinking water per day. In the liver sections of valproic acid group, perivenullar dilatation, swelling of Kuppfer cells, microvesicular steatosis and degeneration were observed. In the second group there was moderate degeneration in hepatocytes,necrotic areas in some places, mononuclear cell infiltration. In valproic acid +vitamin E group normal-like appearance of the structure of Remark cell lines were observed. Under these source of results, we viewed antioxidants decreased the hepatotoxicity on liver tissue by using folic acid and vitamin E .

Keywords:

Folic Acid, Liver, Pregnancy, Valproic Acid, Rats, Wistar, Vitamin E,

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1. Löscler W.H., Nau U., Wahnshaffe D., Hönack C., Rundfeldt W., Wittfoht & Bojic U. Effect of valproate and E-2-en-valproate on functional and morfological parameters of rat liver.II. İnfluence of phenobarbital comedication. Epilepsy. Res. 1993;15: 113-131.
2. Rettie A.E.,Boberg M.,Rettenmeier W.A.&Baillie A.T. Cytochroma P-450- catalyzed desaturation of valproic acid in vitro. J.. Biol. Chem.1988;263:13733-13738.
3. Buchi K.N., Gray P.D., Rollins D.E., Tolman K.G. Protection against sodium valproate ıngury in isolated hepatocytes by alfa-Tocopherol and N.N-Diphenyl-p-phenylenediamine. J.Clin. Pharmacol. 1984;24:148-154.
4. Suchy FJ, Balistereri WF., Buchino J.J. et al. Acute hepatic failure associated with the use of sodıum valproate. N. Engl. J. Med. 1979:300-962.
5. Ware S., Millward-Sadler G.H. Acute liver disease associated with sodium valproate, Lancet.1980;2:1110-1980.
6. Reynolds JEF., Parfitt K., Parsons A.V., Sweetman S.C. editors. Folic Acid. Martindale:The extra Pharmacopoeia. 31sted. London: The Royal Pharmaceutical Society, 1996: 1361-1362.
7. Jurima-Romet M., Abbott F.S., Tang. W., Huang H.S.,Whitehouse L.W. Cytotoxicity of unsaturated metabolites of valproic acid and protection by vitamins C and E in glutathionedepleted rat hepatocytes. Toxicology. 1996;112:69-85.
8. Zimmerman HJ, Ihsak KG. Valproateinduced hepatic injury: analyses of 23 fatal cases. Hepatology.1982;2:591-597.
9. Fenichel GM, Grene HL. Valproate hepatotoxicity: two new cases, a summary of other and recommendations. Pediatr Neural. 1985;1:109-113.
10. Zafrani ES, Berthelot P.Sodium valproate in the induction of unusal hepatotoxicity. Hepatology 1982;2:648-649.
11. Becker C.M., Harris R.A. Influence of valproic acid on hepatic carbonhydrate and lipid metabolism. Arch. Biochem. Biophys.1983;223:381-392.
12. Beers R.F., Sizer W. A spectrophotometric method for measurement the breakdown of hydrogen peroxide by catalase. J. Biol. Chem.1951;195:133-140.
13. Seçkin Ş., Başaran-Küçükgergin C., Uysal M. Effect of acute and chronic administration of sodium valproate on lipid peroxidation and antioxidant system in rat liver. Pharmacol. Toxicol.1999;85:294-298.
14. Daffron J.C. and Kasarkis E.J. Effect of valproic acid on zinc metabolism in the rat. Toxicol. Lett. 1984;23 :321.
15. Keen C.L., Peters J.M. and Hurley L.S. The effect of valproic acid on Zn distribution in the pregnant rat. J. Nutr.1989:119- 607.
16. Browne TR.Valproic acid. N Engl J Med. 1980; 20;302(12):661-6.
17. Zimmerman HJ, Ihsak KG. Valproate induced hepatic injury: analysis of 23 fatal cases. Hepatology. 1982;2: 591-597.
18. Jeavons P.M. Non-dose-related side effects of valproate. Epilepsia.1984;25 (Suppl.1):1153-1158.
19. Nau H., Hauck R.S. and Ehlers K. Valproic acid-induced neural tube defects in mouse and human: Aspects of chirality, alternative drug development, pharmacokinetics and possible mechanisms. Pharmacol. Toxicol. 1991;69: 310-321.
20. Nau H., Siemens H. Differantiation between valproic acid-induced anticonvulsant effect, teratogenicity and hepatotoxicity: aspects of species variation, pharmacokinetics, metabolism and implications of structural specificity for the development of alternative antiepileptic agents such as 2-en-VPA, Pharm. Weekbl. 1992;14:101-107.
21. Kingsley E., Gray PD., Tolman KG., Tweedale R. The toxicity of metabolites of sodium valproate in cultured hepatocytes. J. Clin. Pharmacol.1983;23:178-185.
22. Kuhura T., Matsumoto I. Metabolism of branched medium chain length fatty acid. I. ω- Oxidation of sodium dipropylacetate in rats. Biomed Mass Spectrom..1974;1:291-294.
23. Matsumoto I., Kuhara T., Yoshino M. Metabolism of branched medium chain length fatty acid. II. β-Oxidation of sodium dipropylacetate in rats. Biomed Mass Spectrom..1976;3:235-240.
24. Madsen AC., Gray P., Tolman KG. Effect of microsomal enzyme induction on valproic acid toxicity in rat hepatocyte cultures. Clinical Res. 1981;29:22A.
25. Powell-Jackson P.R., Tredger J.M. and Williams R. Hepatotoxicity to sodium valproate: a review. Gut. 1984;25:673-681.
26. Konig A., Siemes H., Blaker F., Boenigk E., Grob-Selbeck G., Hanefeld F. et al. Severe hepatotoxicity during valproate therapy: an update and report of eight new fatalities. Epilepsia.1994;35:1005-1015.
27. Kochen W., Schneider A. and Ritz A. Abnormal metabolism of valproic acid in fatal hepatic failure. Eur. J. Pediatr. 1983;141:30-35.
28. Siemens H., Nau H., Schultze K., Wittfoht W., Drews E., Penzien J. et al.Valproate (VPA) metabolites in various clinical conditions of probable VPA-associated hepatotoxicity. Epilepsia.1993;34:332-346.
29. Graf W.D., Oleinik O.E., Glauser T.A., Eder D.N. and Pippenger C.E. Altered antioxidant enzyme activities in children with serious adverse experience related to valproic acid therapy. Neuropediatrics.1998;29:195-201.
30. Qureshi I.A., Letarte J., Tuchweber B., Qureshi I.A., Letarte J., Tuchweber B., Ousef I., Qureshi S.R. Hepatotoxicity of sodium valproate in ornithine-transcarboxylase deficient mice. Toxicol. Lett.1985;25 (3): 297.
31. Jeavons P.M.,Woodbury D.M., Penry J.K., Pippenger C.E. (eds.) Valproate. In: “Toxicity in Antiepileptic Drugs”. 2nd Ed. Raven Pres, New York, 1982: 601-610.
32. Cotariu D., Reif R., Zaidman J.L., Evans S. Biochemical and morphological changes induced by sodium valproate in rat liver. Pharmacol. Toxicol. 1987;60 (3): 235.
33. Olson M.J., Handler J.A., Thurman R.G. Mechanism of zone spesific hepatic steatosis caused by valproate:İnhibition of ketogenesis in periportal regions of the liver tubule. Moleculer Pharmacol. 1986;30(6):520.
34. United States Pharmacopoeia Dispensing İnformation. Vol.1: Drug information for the Health Care Professional. 16th ed. Rockville, Maryland: United States Pharmacopoeial Convention Inc.;1998.
35. Reynolds JEF., Parfitt K., Parsons A.V., Sweetman S.C. editors. Folic Acid. Martindale:The extra Pharmacopoeia. 31th ed. London: The Royal Pharmaceutical Society. 1996: 1361-1362.
36. Komatsu M., Tsukamoto I. Effect of folic acid on thymidylate synthase and thymidine kinase in regenerating rat liver after partial hepatectomy. Biochimica et Biophysica Acta (BBA)- General Subjects.1998; 2:289-296.
37. Lombardi B., Chander N. & Locker J. Nutritional model of carcinogenesis; rats fed a choline devoid diet. Dig.Dis. Sci.1991; 36:979- 984