Fluoksetinin deneysel verilmesinden sonra sıçan karaciğerinin histopatolojik incelenmesi

Öz

Objective: To investigate the histopathological changes in the liver after experimental application of fluoxetine. Materials and methods: Nineteen male and 24 female rats of Sprague-Dawley strain were used to study the effect of administration of fluoxetine over a period of 3 weeks. The rats were randomly divided into five groups. Groups A to group D, each consisting of 10,10, 10, 7 rats respectively, were for different tests, while 6 rats were used as normal controls (N). For group A,B,C,D fluoxetine was administered via intraperitoneal enjection at a dosage of 5 mg/kg, 7.5 mg/kg, 10 mg/kg, 25 mg/kg, respectively. The experiment lasted 3 weeks. Hepatic tissue samples were extracted under anesthesia for histopathologic study. Liver tissues were fixed in 10% buffered formalin and embedded in paraffin. Histopathologic changes were evaluated on the H&E stained sections. Results: The major histopathological changes in the liver after fluoxetine are hydropic degeneration, karyomegaly, steatosis, lobuler inflammation, focal necrosis, apoptosis, disruption, twinning cell plates, cholestasis, portal area inflammation, Kupffer cell hyperplasia and double nucleus (P<0.05). Conclusion: Our results show that exposure of rats to fluoxetine leads to toxic effects. At the end of the exposure period, livers of all exposed rats, but no controls, showed hydropic degeneration, karyomegaly, steatosis, lobular inflammation, focal necrosis, apoptosis, disruption, apopitoz, ayrışma, çift hücre kordonları, kolestaz, portal twinning cell plates, cholestasis, portal area inflammation, alanda inflamasyon, Kupffer hücrelerinde hiperplazi ve Kupffer cell hyperplasia and double nucleus. The main histopathological changes in all exposed rats were histopatolojik değişiklik hepatosellüler hidropik vakuoler hepatocellular hydropic vacuolar degeneration (%100). dejenerasyondur (%100)

Anahtar Kelimeler

• rat liver, fluoxetine, hepatotoxicity, degeneration, antidepressants

Histopathologic examination of rat liver after experimental application of fluoxetine

Öz

Amaç: Deneysel olarak fluoksetin verilmesinden sonra karaciğerdeki histopatolojik değişiklikleri araştırmak. Gereç ve yöntem: Sprague-Dawley cinsinden 19 dişi ve 24 erkek rata 3 hafta süresince verilen fluoksetinin etkileri incelendi. Ratlar rastgele 5 gruba ayrıldı. Grup A’dan D’ye kadar her grupta sırasıyla 10, 10, 10, 7 rat vardı. Her gruba farklı test uygulandı ve 6 rat normal kontrol grubu olarak kullanıldı (N). A, B, C, D gruplarına sırasıyla intraperitoneal enjeksiyon yoluyla 5 mg/kg, 7,5 mg/kg, 10 mg/kg, 25 mg/kg fluoksetin verildi. Deneyden 3 hafta sonra karaciğer örnekleri histopatolojik inceleme için anestezi altında alındı. Karaciğer dokuları %10’luk buffer formalinde tespit ettikten sonra parafine gömüldü. Histopatolojik değişiklikler H+E boyalı kesitlerde değerlendirildi. Sonuç: Fluoksetin verildikten sonra karaciğerdeki başlıca histopatolojik değişiklikler hidropik dejenerasyon, karyomegali, yağlanma, lobular inflamasyon, fokal nekroz, apopitoz, ayrışma, çift hücre kordonları, kolestaz, portal alanda inflamasyon, Kupffer hücrelerinde hiperplazi ve çift nukleusdu (p<0.05). Tartışma: Sonuçlarımız da ratların fluoksetine maruz kalması toksik etkilere yol açtığı görülmüştür. Deney sonunda, kontrol grubu dışında bütün maruz kalan ratların karaciğerlerinde hidropik dejenerasyon, karyomegali, yağlanma, lobular inflamasyon, fokal nekroz

Anahtar Kelimeler

• Rat karaciğeri, fluoksetin, hepatotoksik, dejenerasyon, antidepresanlar

Kaynakça

1. Cai Q, Benson MA, Talbot TJ, Devadas G, Swanson HJ, Olson JL, Kirchner JP. Acute hepatitis due to fluoxetine therapy. Mayo Clin Proc 1999; 74: 692-694.
2. Stokes PE, Holtz A. Fluoxetine tenth anniversary uptake: The progress continues. Clin Ther 1997; 19: 1135-1150.
3. Schmidt MJ, Fuller RW and Wong DT. Fluoxetine, a highly selective serotonin reuptake inbition: A review of preclinical studies. Br J Psychiatry 1988; 153: 40-46.
4. Caccia S, Cappi M, Fracasso C, Garattini S. Influence of dose and route of administration on the kinetics of flu- oxetine and its metabolite norfluoxetine in the rat. Psycho- pharmacology 1990; 100: 509-514.
5. Parli CJ and Hicks J. In vivo demethylation of Lilly 110140: 3-(p-trifluoromethylphenoxy)-N-methyl-3-phenylpropylamine to an active metabolite Lilly 103947. Fedn Proc 1974; 33: 560.
6. Morgan JF. Fluoxetine and eating disorders. Hospital Medicine 1999; 60: 686.
7. Stark P, Fuller RW and Wong DT. The pharmacologic profile of fluoxetine. J Clin Psychiatr 1985; 46: 7-13.
8. Lemberger L, Farid NA, Bergstrom RF, Wolen RL. Flu- oxetine pharmacology and physiologic disposition. Int J Obesity 1987; 11: 157-161.

9. Waldinger MD, Helgeveld MW, Zwinderman AH, Olivier B. Effect of SSRI antidepressants on ejaculation: a double- blind, randomized, placebo-controlled study with fluoxetine, fluvoxamine, paroxetine and sertraline. J Clin Psychopharmacol 1998; 18: 274-281.
10. Vom Dahl S, Hallbrucker C, Lang F, Gerok W, Haussinger
11. Mars F, Dumas de la Roque G and Goissen P. Hepatite aigue lors du traitement par la fluoxetine. Gastroenterol Clin Biol 1991; 15: 270-271.
12. Bendele RA, Adams ER, Hoffman WP, Gries CL, Morton DM. Carcinogenicity studies of fluoxetine hydrochloride in rats and mice. Cancer Res 1992; 52: 6931-6935.
13. Lazaros GA, Stavrinos C, Papatheodoridis GV, Del- ladetsima JK, Toliopoulos A, Tassopoulos NC. Amineptine induced liver injury: report of two cases and brief review of the literature. Hepatogastroenterology 1996; 43: 1015-1019.
14. Castiella A and Arenas JI. Fluoxetine hepatotoxicity. Am J Gastroenterol. 1994; 89: 458-459.
15. O’Connor MJ, Sumner HW and Schwartz ML. The clinical and pathological correlation in mechanical biliary obstruc- tion and acute cholangitis. Ann Surg 1982; 195: 419-423.
16. Edomondson HA, Schiff L and Schiff ER. Needle biopsy of the liver, Diseases of the Liver, 5th ed. Philadelphia, Lipincott, 1982; 303332.
17. Pavanato A, Tunon MJ, Sanchez-Compos S, Marroni CA, Llesuy S, Gonzalez-Gallego J, Marroni N. Effects of quercetin on liver damage in rats with carbon tarachloride- induced cirrhosis. Dig Dis Sci 2003; 48: 824-829.
18. Zimmerman HJ. Hepatotoxicity: The Adverse Effects of Drugs and Other Chemicals on the Liver, New York, NY: Appleton-Centrury-Crofts, 1978; 360-362.
19. Capelle D, Bruguera M, Figueras A, Laporte JR. Flu- oxetine-induced hepatitis: why is postmarketing surveil- lance needed? Eur J Clin Pharmacol. 1999; 55: 545-546.
20. Bobichon R, Bernard G and Mion F. Atteinte hepatique aigue lors d’un traitement par la fluoxetine. Gastroenterol Clin Biol 1993; 17: 406-407.
21. Johnston DE and Wheeler DE. Chronic hepatitis related to use of fluoxetine. AJG 1997; 92: 1225-1226.
22. Cosme A, Barrio J, Lob C, Gil I, Castiella A, Arenas JI. Acute cholestasis by fluoxetine. Am J Gastroenterol. 1996; 91: 2449-2450.
23. Wilson T, Rabie CJ, Fincham JE, Steyn PS, Schipper MA. Toxicity of rhizonin A, isoleted from Rhizopus microsporus, in laboratory animals. Food Chem Toxicol 1984; 22: 275-281.
24. Kawata N, Tsuge H, Gouchi A, Nakagou R, Naomoto Y, Tanaka N. Vacuolar hepatocyte degeneration induced by infusion of 20% glucose solution with insulin after hepato- pancreatectomy in rats. Int Med Res 2000; 28: 168-181.
25. Haussinger D, Lang F and Gerok W. Regulation of cell function by the cellular hydration state. Am J Physiol 1994; 267: E343-E355.
26. Hallbrucker C, Vom Dahl S, Lang F, Gerok W, Haussinger. Inhibition of hepatic proteolysis by insulin: role of hormone induced alterations of cellular K+ balance. Eur J Biochem 1991; 199: 467-474. D. Regulation of liver cell volume and proteolysis by glu- cagon and insulin. Biochem J 1991; 278: 771-777.
27. Vom Dahl S, Hallbrucker C, Lang F, Haussinger D. Re- gulation of cell volume in the perfused rat liver by hor- mones. Biochem J 1991; 280: 105-109.
28. Edgar VA, Genaro AM, Cremaschi G, Sterin-Borda L. Fluoxetine action on murine T-lymphocyte proliferation: participation of PKC activation and calcium mobilisation. Cell Signal 1998; 10: 721-726.
29. Edgar VA, Sterin-Borda L, Cremaschi GA, Genaro AM. Role of protein kinase C and CAMP in fluoxetine effects on human T-cell proliferation. Eur J Pharmachol 1999; 372: 65-73.
30. Genaro AM, Edgar VA and Sterin-Borda L. Differential effects of fluoxetine on murine B-cell proliferation depen- ding on the biochemical pathways triggered by distinct mitogens. Biochem Pharmacol 2000; 60: 1279-1283.
31. Corresponding author
32. Kısmet Bildirici, MD
33. Akarbaşı Mah. Arısoy Sok. Ayseana Sitesi No:19 B Blok D:8 Eskisehir/ Turkey.
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