THE EFFECTS OF L-ASCORBIC ACID ON ISONIAZID-INDUCED PROTEIN OXIDATION AND HEPATOTOXICITY IN RATS

Yıl 2024, Cilt: 4 Sayı: 9, 1 - 7, 07.02.2024

Habibe Genç , Şeyma Dümür , Yakup Ergül , Yusuf Elgörmüş , Hafize Uzun

https://doi.org/10.54270/atljm.2023.46

Öz

Isoniazid (INH) is hepatotoxic drug. Oxidative stress has been reported as one of the mechanisms of INH induced hepatotoxicity. In the current study, our aim was to evaluate the redox status of plasma and liver proteins as well as the protective role and dose of ascorbic acid (AA) in INH-induced hepatotoxicity in rats. Protein oxidation parameters such as protein carbonyl (PCO), total thiol (T-SH) levels and paraoxonase-1 (PON-1) activity was determined in the liver and the plasma of rats. Rats under study were randomly divided into four groups: (1) control; (2) INH (50mg/kg/day); (3) INH (50mg/kg/day) + AA (100 mg/kg/day); and (4) INH + AA (1000 mg/kg/day). INH administration resulted in abnormal elevation of plasma and hepatic PCO levels. On the other hand, the levels of the plasma and hepatic T-SH and PON1 activity significantly decreased. Supplementation of AA (100 mg/kg/day) dose partially reverted these abnormalities in the redox status of the proteins and activities of PON1 after the administration of INH. Changes in oxidative stress are likely involved in the pathogenesis of INH-induced hepatoxicity in rats.

Anahtar Kelimeler

Askorbik asit, İzoniazid, Paraoksonaz, Protein karbonil, Total tiyol, Protein oksidasyonu

THE EFFECTS OF L-ASCORBIC ACID ON ISONIAZID-INDUCED PROTEIN OXIDATION AND HEPATOTOXICITY IN RATS

Öz

İzoniazid (INH) hepatotoksik bir ilaçtır. Oksidatif stres, INH kaynaklı hepatotoksisitenin mekanizmalarından biri olarak rapor edilmiştir. Çalışmada amacımız, sıçanlarda INH kaynaklı hepatotoksisitede askorbik asid (AA)'in koruyucu rolü ve dozunun yanı sıra plazma ve karaciğer proteinlerinin redoks durumunu değerlendirmekti. Sıçanların karaciğer ve plazmalarında protein karbonil (PCO), total tiol (T-SH) seviyeleri ve paraoksonaz-1 (PON-1) aktivitesi gibi protein oksidasyon parametreleri belirlendi. Sıçanlar rastgele dört gruba ayrıldı: (1) kontrol; (2) INH (50mg/kg/gün); (3) INH (50mg/kg/gün) + AA (100 mg/kg/gün); ve (4) INH + AA (1000 mg/kg/gün). INH uygulaması, plazma ve hepatik PCO düzeylerinde anormal yükselme ile sonuçlanmıştır. Aynı zamanda, plazma ve hepatik T-SH seviyeleri ve PON1 aktivitesi önemli ölçüde azaldı. AA (100 mg/kg/gün) dozu takviyesi, proteinlerin redoks durumundaki ve INH uygulamasından sonra PON1 aktivitelerindeki bu anormallikleri kısmen geri döndürdü. Oksidatif stresteki değişiklikler muhtemelen sıçanlarda INH kaynaklı hepatoksisitenin patogenezinde yer almaktadır.

Anahtar Kelimeler

Askorbik asit, İzoniazid, Paraoksonaz, Protein karbonil, Total tiyol, Protein oksidasyonu

Kaynakça

• Global Tuberculosis Control Report, World Health Organisation, 2008 [Homepage on the Internet]. [Last updated July 09, 2008; Cited July 09, 2008] Available from: http://www.who.int
• Tafazoli S, Mashregi M, O’Brien PJ. Role of hydrazine in isoniazid-induced hepatotoxicity in a hepatocyte inflammation model. Toxicol Appl Pharmacol 2008; 229: 94-101.
• Stadtman ER, Levine RL. Chemical modification of proteins by reactive species. In: Dalle- Donne I, Scaloni A, Butterfield DA (eds.) Redox Proteomics. Wiley-Interscience, New Jersey. 2006. Ch. 1.
• Sethuraman M, McComb ME, Huang H, Huang S, Heibeck T, Costello CE, Cohen RA. ICAT (Isotope-coded affiniy tag) approach to redox proteomics: Identification and quantification of oxidant-sensitive protein thiols. In: Dalle-Donne I, Scaloni A, Butterfield DA. (eds.) Redox Proteomics. Wiley-Interscience, New Jersey. 2006. Ch. 10.
• Jaouad L,Guise C, Berrougui H, Cloutier M, Isabelle M, Fulop T, Payette H, Khalil A. Age-related decrease in high-density lipoproteins antioxidant activity is due to an alteration in the PON1’s free sulfhydyl groups. Atherosclerosis 2006; 185: 191-200.
• Gugliucci A, Lunceford N, Kinugasa E, Ogata H, Schulze J, Kimura S. Acrolein inactivates paraoxonase 1: changes in free acrolein levels after hemodialysis correlate with increases in paraoxonase 1 activity in chronic renal failure patients. Clin Chim Acta 2007; 384: 105-112.
• Costa LG, Vitalone A, Cole TB, Furlong CE. Modulation of paraoxonase (PON1) activity. Biochem Pharmacol 2005; 69: 541-550. Dragsted LO. Biomarkers of exposure to vitamins A, C, and E and their relation to lipid and protein oxidation markers. 2008; Eur J Nutr 47 (Suppl 2): 3–18.
• Sodhi CP, Rana SV, Mehta SK, Vaiphei K, Attari S, Mehta S. Study of oxidative-stress in isoniazid-rifampicin induced hepatic injury in young rats. Drug Chem Toxicol 1997; 20: 255-269.
• Adeneye AA, Olagunju JO. Protective Effect of Oral Ascorbic Acid (Vitamin C) Against Acetaminophen-Induced Hepatic Injury in Rats. Af J Biomed Res 2008; 11: 183-190.
• Reznick AZ, Packer L. Oxidative damage to proteins: spectrophotometric method for carbonyl assay. Methods Enzymol 1994; 233: 357-363.
• Hu ML. Measurement of protein thiol groups and glutathione in plasma. Methods Enzymol. 1994; 233: 381-385.
• Sedlak J, Lindsay RH. Estimation of total, protein bound, and non-protein sulfhydryl groups in tissue with Ellman’s reagent. Anal Biochem 1968; 25: 192-205.
• Hasselwander O, Savage DA, McMaster D, Loughrey CM, Mcnamee PT, Middleton D, Nicholls DP, Maxwell AP, Young IS. Paraoxonase polymorphism are not associated with cardiovascular risk in renal transplant recipients. Kıdney Int 1999; 56: 289-298.
• Saha N, Roy AC, Teo SH, Tay JS, Ratnam SS. Influence of serum paraoxonase polymorphism on serum lipids and apolipoproteins. Clin Genet 1991; 40: 277-282.
• Hussain SM, Frazier JM. Cellular toxicity of hydrazine in primary rat hepatocytes. Toxicol Sci 2002; 69: 424-432.
• Tafazoli S, O’Brien PJ. Accelerated cytotoxic mechanism screening of hydralazine using an in vitro hepatocyte inflammatory cell peroxidase model. Chem Res Toxicol 2008; 21: 904- 910.
• Fere N, Camps J, Cabre M, Paul A, Joven J. Hepatic paraoxonase activity alterations and free radical production in rats with experimental cirrhosis. Metabolism 2001; 50: 997-1000.
• Beltowski J, Jamroz-Wisniewska A, Borkowska E, Wojcicka G. Differential effect of antioxidant treatment on plasma and tissue paraoxonase activity in hyperleptinemic rats. Pharmacol Res 2005; 51: 523-532.
• Park SW, Lee SM. Antioxidant and prooxidant properties of ascorbic acid on hepatic dysfunction induced by cold ischemia/reperfusion. Eur J Pharmacol 2008; 580: 401-406.