Ertuğrul Emre GÜNTÜRK, Bilal YÜCEL, Inayet GUNTURK, Cevat YAZICI, Kader KÖSE

Sisplatin kardiyotoksisitesinde oksidatif ve nitrozatif stresin rolü

Amaç: Sisplatin solid organ tümörlerinin tedavisinde yaygın olarak kullanılan, oldukça etkili bir kemoterapötik ajandır. Ancak klinik kullanımını sınırlayan yan etkileri mevcuttur ve bunların arasında kardiyotoksisite son yıllarda özellikle gündeme gelmiştir. Kardiyotoksisite gelişimine katkı sağlayan en önemli mekanizmaların da oksidatif ve nitrozatif stres olduğu öne sürülmektedir. Dolayısıyla kardiyotoksisitenin önüne geçilmesinde antioksidanların kullanımı ön plana çıkmaktadır. Klinikte farklı patolojilerde yaygın olarak kullanılan N-asetilsistein (NAC), doğrudan radikal yakalayıcı olarak ve/veya hücre içi redükte glutatyon düzeylerini artırarak etki gösteren güçlü bir antioksidandır. Bu çalışmada, NAC’ın ratlarda sisplatinle indüklenen kardiyotoksisite üzerine etkilerinin araştırılması amaçlanmıştır. Yöntem: Bu amaçla, her grupta sekiz hayvan olmak üzere, ratlar dört gruba ayrıldı: KONT, NAC-250, CP ve CP+NAC. Sisplatin uygulaması intraperitoneal (ip) tek doz, 10 mg/kg rat ağırlığı ve NAC uygulaması ip, ardışık üç gün, 250 mg/kg rat ağırlığı şeklinde yapıldı. Kan örneklerinde CK, CK-MB, İskemi Modifiye Albümin (İMA); doku örneklerinde 4-Hidroksinonenal (4-HNE) ve 3-Nitrotirozin (3-NT) seviyeleri ölçüldü. Bulgular: CP grubunda kontrole göre artan CK ve CK-MB düzeyleri ile kardiyotoksisite gelişimi gösterildi. Yine CP grubunda İMA, 4-HNE ve 3-NT seviyelerinin de arttığı ortaya konuldu. Bununla birlikte sisplatin ile birlikte NAC uygulaması ile tüm parametrelerde anlamlı azalma gösterildi. Sonuç: Sisplatin kardiyotoksisitesi gelişiminde oksidatif ve nitrozatif stresin rol oynadığı; bu toksik tabloyu önlemede, NAC’ın etkili bir kemoprotektan ajan olarak kullanılabileceği söylenebilir.

Anahtar Kelimeler:

Rat, sisplatin, oksidatif stres, nitrozatif stres, N-asetilsistein

The role of oxidative and nitrozative stress in sisplatin cardiotoxicity

Objective: Cisplatin is a highly effective chemotherapeutic agent widely used in the treatment of solid organ tumors. However, there are side effects that limit its clinical use and among them, cardiotoxicity has been particularly on the agenda in recent years. It is suggested that the most important mechanisms that contribute to the development of cardiotoxicity are oxidative and nitrosative stress. Therefore, the use of antioxidants comes to the fore in preventing cardiotoxicity. N-acetylcysteine (NAC), widely used in different pathologies in the clinic, is a powerful antioxidant that acts as a direct radical trap and/or by increasing intracellular reduced glutathione levels. In the current study, it was aimed to investigate the effects of NAC on cisplatin-induced cardiotoxicity in rats. Methods: For this purpose, rats were divided into four groups, eight animals in each group: CONT, NAC-250, CP, and CP+NAC. Cisplatin administration was performed as intraperitoneal (IP) single dose, 10 mg/kg rat weight and NAC administration IP, 3 consecutive days, 250 mg/kg rat weight. In blood samples, CK, CK-MB, and Ischemia Modified Albumin (IMA) levels; in tissue samples, 4-Hydroxynonenal (4-HNE) and 3-Nitrotyrosine (3-NT) levels were measured. Results: in the CP group cardiotoxicity development was demonstrated with increased CK and CK-MB levels compared to the control. It was also demonstrated that IMA, 4-HNE and 3-NT levels increased in the CP group. However, NAC administration with cisplatin showed a significant decrease in all parameters. Conclusion: Oxidative and nitrosative stress played a role in the development of cisplatin cardiotoxicity; It can be said that NAC can be used as an effective chemoprotectant agent in preventing this toxic picture.

Keywords:

Rat, cisplatin, oxidative stress, nitrosative stress, N-acetylcysteine,

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