Isoniazid Induced Toxicities and Idiosyncratic Responses in Male Albino Wistar Rats
Keywords:Isoniazid, Tuberculosis, Mycobacterium tuberculosis, hepatotoxicity, genotoxicity, carcinogenesis.
Isoniazid (INH) is an anti-tuberculosis drug administered over a long period. Upon metabolism in the liver, INH generates nitrogen-centered radicals, reacting with cellular macromolecules, and induces toxic and transformational changes in cells and tissues. Here we examined the side effects of long-term (chronic) administration of isoniazid (2.5 and 5mg/kg) once daily for 30, 60 and 90 days consecutively: on hepatic transaminases, histological changes in hepatocytes and induction of micronuclei in the bone marrow and possible genotoxicity in E. coli PQ37. In addition, blood glucose was monitored during the various treatment period. Biochemical analysis of hepatic transaminases (γ-glutamyl-, alanine amino-, aspartate aminotransferases and alkaline phosphatase) in INH treated group was significantly (p<0.05) elevated as well as blood glucose level declined significantly (p<0.05) for both doses at 30, 60 and 90 treatment respectively. Total protein and albumin level decreased (p<0.05) at both treatment doses compared to control. Serum creatinine level significant (p<0.05) increased at days 30 and 60 relative to control.Antioxidants (GST, SOD and catalase) activity examined indicated a decrease in catalase levels which was significant (p<0.05) and an insignificant decrease (p>0.05) in GST in both treatment groups at day 60. There was also a significant increase (p<0.05) in the activity of superoxide dismutase activity. Micronucleus analysis further revealed an induction of micronucleated polychromatic erythrocytes (mPCEs), which was significant (p<0.05) for both treatment doses at days 30, 60 and 90 respectively. In addition, INH genotoxicity assessed by UMU chromotest indicated that the 5mg/kg dosage has an induction ratio above the genotoxicity threshold of 1.5 suggesting genotoxicity in E.coli PQ37.Taken together, INH treatment at both doses (2.5 and 5mg/kg body weight) was hepatotoxic and induced nephrotoxic damages, in addition to mutagenic effect which is more pronounced at 2.5mg/kg dose, thereby suggesting dose-dependent cellular and genetic toxicity.
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