Toxicity of some broad-spectrum antibacterials in normal rat liver: the role of mitochondrial membrane permeability transition pore

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Abstract
Ciprofloxacin (CIP) and Amoxycillin/Clavulanate (AC) are broad-spectrum antibiotics that are commonly administered for treatment of various bacterial infections. Studies have reported the antiproliferative and apoptotic activities of CIP in several cancer cell lines while AC has been implicated in drug–induced liver injury. We investigated the influence of CIP and AC on mitochondrial Permeability Transition (mPT) pore, ATPase activity, and cytochrome C release of normal Rat Liver Mitochondria (RLM) spectrophotmetrically. In vitro, CIP and AC induced the opening of the mPT pore in a concentration-dependent manner with evidence of cytochrome C release maximally at 70µg/ml by 13 and 10 folds, respectively. In vivo, CIP (100, 200 mg/kgbw) significantly induced mPT pore opening with induction folds of 2.4 and 2.6, respectively. However, low dose of AC (10mg/kgbw) had no effect whatsoever on the mPT pore while higher dose (30 mg/kgbw) significantly induced pore opening by 3.4 folds. Similarly, CIP(100 mg/kgbw) and AC (30 mg/kgbw), doses selected for further studies, significantly enhanced RLM ATPase activity, induced cytochrome C release and increased levels of RLM malondialdehyde generated . Significant (p < 0.05) elevation in levels of aminotransferases and white blood cell count were observed which resulted in activation of caspase-9 and 3 in liver post-mitochondrial fraction. Our results show that prolonged use of Ciprofloxacin and Amoxicillin Clavulanate could result in mitochondrial membrane breakdown via induction of opening of mPT pore leading to expulsion of cytochrome C, lipid peroxidation and decrease in energy content in healthy liver cells. Indiscriminate use of these drugs is hereby discouraged.

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