Parakuat'ın nefrotoksik etkisine Asetaminofen'in katkısının sıçanlarda enzimüri ile izlenmesi
Küçük Resim Yok
Tarih
2000
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Cilt Başlığı
Yayıncı
Ege Üniversitesi
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
103 ÖZET Nefrotoksik maddelerle yapılan in vivo deneysel çalışmalarda, üriner enzimlerin atılımındaki artışların tübüler hasann işaretçisi olduktan belirtilmiştir. Bu çalışmada; Parakuat (PK) ve Asetaminofen (APAP)'in sıçan böbreği üzerindeki akut toksik etkilerinin erken tanısında yardımcı olmak üzere, fırçasal kenar enzim Gamma- Glutamil Transpeptidaz (GGTP) ve lizozomal enzim N-Asetil-p-D-Glukozaminidaz (NAG)'ın idrardaki akövite tayinlerinin araştırılması amaçlanmıştır. Ayrıca, renal fonksiyonların izlenmesinde klasik olarak başvurulan bazı biyokimyasal parametrelerin ölçümlerine de (idrarda protein, serumda kreatinin ve kan üre azotu=BUN) yer verilmiştir. Çalışma, toplam on grupta Swiss-Albino türünden 108 adet erkek sıçan üzerinde gerçekleştirilmiştir. Kontrol grubu dışındaki deney gruplarına, 40 mg/kg PK (PK grubu) ya da 250, 500, 750 veya 900 mg/kg APAP (APAP-250, APAP-500, APAP-750, APAP-900 gruplan), kombine gruplara ise 40 mg/kg PK verilmesinin ardından 250, 500, 750 veya 900 mg/kg APAP (PK+APAP-250, PK+APAP-500, PK+APAP-750, PK+APAP-900 grupları) intraperitonal olarak uygulanmıştır. Üriner GGTP atılımında ilaç verilen tüm gruplarda, üriner NAG atılımında APAP-250 grubu dışındaki (250 mg/kg APAP verilen) diğer tüm gruplarda, kontrol grubuna göre ileri derecede artışlar meydana gelmiştir (p<0.0001). Total üriner protein atlımı ağsından kontrol grubu ile karşılaştırıldığında, PK verilen grup dışında diğer tüm ilaç verilen gruplarda, idrar protein atılımında ileri derecede artışlar meydana gelmiştir (p<0.0001). Serum kreatinin düzeylerinde, PK grubunda ve en yüksek dozda APAP verilen grupta (APAP-900) kontrol grubuna göre anlamlı artışlar saptanmıştır (p<0.01). Benzer şekilde, BUN düzeylerinde de, PK ve APAP-900 gruplarında anlamlı artışlar saptanmıştır104 (p<0.001). PK + APAP verilen kombine grupların hepsinde, her iki parametre açısından anlamlı artışlara ulaşılmıştır (p<0.001). Böbrek dokulannın histopatolojik inceleme sonuçlan, PK ve APAPIn nefronun proksimal tübüllerinde nekroz ve dejenerasyona neden olduğunu ortaya koymuştur. Ancak, histopatolojinin, farklı dozlarda APAPIn ve her iki ilacın kombine uygulanmasının neden olduğu nefrotoksik etkileri belirlemede yetersiz kaldığı görülmüştür. Bu çalışmada, PK ve APAP enjekte edilen sıçanlarda böbrek hasarının izlenmesinde en duyarlı, en erken işaretçilerin, enzimlerin üriner atlımındaki artışlar ile üriner protein atılımı olduğu sonucuna varılmıştır. Erken dönemde gözlenen proteinüri ve enzimüriyi, serum BUN ve kreatinindeki anlamlı artışlar izlemiş, ancak histopatolojik bulgular ile enzimüri arasında korelasyon bulunamamıştır. Enzimlerin idrarda atılımlarında gözlenen artışlar; 1) PK ve APAPIn nefrotoksik etkilerinin doza bağlı olduğunu, 2) ilaçların tek başına ve birlikte indüklediği nefrotoksisitenin izlenmesinde GGTP ve NAG'ın idrardaki aktivite tayinlerinin yararlı birer nefrotoksisite işaretçisi olarak kullanılabileceğini, 3) ilaca ve/veya doza bağlı olarak indüklenen nefrotoksik etkide, her iki enzimin üriner atılımında farklılıklar ve hassasiyetler ortaya çıkabileceğini göstermiştir. Ayrıca, APAPIn, PK'ın nefrotoksik etkisine ek (aditif) bir nefrotoksik katkısının olduğu ve aditif toksik etkinin belirlenmesinde proteinürinin enzimüriden daha hassas olduğu belirlenmiştir
105 SUMMARY In vivo studies done with nephrotoxic substances demonstrated that increases in excretion of urinary enzymes were markers of tubular damage. This study investigates the activities of Gamma-Glutamyl Transpeptidase (GGTP), a brush border enzyme, and N-acetyl-p-D-Glucosaminidase (NAG), a lysosomal enzyme, in urine in order to improve the early determination of the acute toxic effects of paraquat (PK) and acetaminophen (APAP) in rat kidney. Some biochemical parameters (protein in urine, serum creatinine and Wood urea nitrogen=BUN) were also measured to monitor renal functions. In this study, 108 male Swiss-Albino rats were used in ten groups. Except for tiie control group, treated groups recaved 40 mg/kg PK (PK group) or 250, 500, 750 or 900 mg/kg APAP (APAP-250, APAP-500, APAP-750, APAP-900 groups), infaperitoneally (i.p.). Combined groups also received 40 mg/kg PK then 250, 500, 750 or 900 mg/kg, i.p., APAP (PK+APAP-250, PK+APAP-500, PK+APAP-750, PK+APAP-900 groups). Urinary excretion of GGTP and NAG increased significantly in all groups treated with the drugs, (p<0.0001, comparable to control). However, NAG excretion did not increase significantiy in APAP-250 group. Total urinary protein excretion increased in all groups treated with APAP and PK+APAP (p<0.0001, comparable to confrol). This parameter did not increase significantiy in PK-treated groups. Serum creatinine levels increased in PK group and the highest dose received APAP group (p<0.01, comparable to control). Similarly, BUN levels increased significantly in PK and APAP-900 group (p<0.001). Both parameters increased significantiy in all PK+APAP (combined) groups (P<0.001).106 Histopathological results of kidney tissues demonstrated that PK and APAP caused proximal tubular necrosis and degeneration in nephrons. However, histopathological examination was found to be inadequate in determination of nefrotoxicity caused by different doses of APAP and combined drug treatment. Based -on this study we conclude that increases in urinary excretions of enzymes and proteins are the most sensitive early determinants in monitoring kidney damage in PK and APAP-treated rats. Increases in protein and enzyme excretions observed at early onset of renal damage were followed by significant increases serum BUN and creatinine; however, no correlation was found between histopathological findings and increase in urinary enzyme excretion. Increases observed in urinary excretion of enzymes demonstrated that 1) nephrotoxic effects of PK and APAP are dose-dependent, 2) the determination of GGTP and NAG activities in urine is a helpful method in monitoring of nephrotoxicity induced by a single drug or drug combinations, and 3) alterations in urinary excretions of these two enzymes and changes in sensitivity can be observed during drug- or dose-dependent nephrotoxicity induced by a drug or drug combinations. In addition to these APAP may contribute to the nephrotoxicity caused by PK and this additive effect can be determined more sensitively by urinary increases in protein excretions than that in enzymes.
105 SUMMARY In vivo studies done with nephrotoxic substances demonstrated that increases in excretion of urinary enzymes were markers of tubular damage. This study investigates the activities of Gamma-Glutamyl Transpeptidase (GGTP), a brush border enzyme, and N-acetyl-p-D-Glucosaminidase (NAG), a lysosomal enzyme, in urine in order to improve the early determination of the acute toxic effects of paraquat (PK) and acetaminophen (APAP) in rat kidney. Some biochemical parameters (protein in urine, serum creatinine and Wood urea nitrogen=BUN) were also measured to monitor renal functions. In this study, 108 male Swiss-Albino rats were used in ten groups. Except for tiie control group, treated groups recaved 40 mg/kg PK (PK group) or 250, 500, 750 or 900 mg/kg APAP (APAP-250, APAP-500, APAP-750, APAP-900 groups), infaperitoneally (i.p.). Combined groups also received 40 mg/kg PK then 250, 500, 750 or 900 mg/kg, i.p., APAP (PK+APAP-250, PK+APAP-500, PK+APAP-750, PK+APAP-900 groups). Urinary excretion of GGTP and NAG increased significantly in all groups treated with the drugs, (p<0.0001, comparable to control). However, NAG excretion did not increase significantiy in APAP-250 group. Total urinary protein excretion increased in all groups treated with APAP and PK+APAP (p<0.0001, comparable to confrol). This parameter did not increase significantiy in PK-treated groups. Serum creatinine levels increased in PK group and the highest dose received APAP group (p<0.01, comparable to control). Similarly, BUN levels increased significantly in PK and APAP-900 group (p<0.001). Both parameters increased significantiy in all PK+APAP (combined) groups (P<0.001).106 Histopathological results of kidney tissues demonstrated that PK and APAP caused proximal tubular necrosis and degeneration in nephrons. However, histopathological examination was found to be inadequate in determination of nefrotoxicity caused by different doses of APAP and combined drug treatment. Based -on this study we conclude that increases in urinary excretions of enzymes and proteins are the most sensitive early determinants in monitoring kidney damage in PK and APAP-treated rats. Increases in protein and enzyme excretions observed at early onset of renal damage were followed by significant increases serum BUN and creatinine; however, no correlation was found between histopathological findings and increase in urinary enzyme excretion. Increases observed in urinary excretion of enzymes demonstrated that 1) nephrotoxic effects of PK and APAP are dose-dependent, 2) the determination of GGTP and NAG activities in urine is a helpful method in monitoring of nephrotoxicity induced by a single drug or drug combinations, and 3) alterations in urinary excretions of these two enzymes and changes in sensitivity can be observed during drug- or dose-dependent nephrotoxicity induced by a drug or drug combinations. In addition to these APAP may contribute to the nephrotoxicity caused by PK and this additive effect can be determined more sensitively by urinary increases in protein excretions than that in enzymes.
Açıklama
Anahtar Kelimeler
Eczacılık ve Farmakoloji, Pharmacy and Pharmacology