Protective effect of lipoic acid against methotrexate-induced oxidative stress in liver mitochondria.
Methotrexate (MTX) is a folic acid antagonist widely used as a cytotoxic chemotherapeutic agent for leukemia and other malignancies. The purpose of this study was to investigate the damage caused by MTX on liver mitochondria and its protection by using antioxidant properties of lipoic acid. MTX substantially affects mitochondrial function by reducing glutathione levels leading to disturbances in antioxidant enzyme defense system. Lipoic acid occurs naturally in mitochondria as a coenzyme. In various studies lipoic acid has been convincingly shown to exhibit an antioxidant role when supplemented exogenously. We studied the effect of lipoic acid pre-treatment on the toxicity of MTX in mouse liver mitochondria focusing specifically on the oxidative stress. MTX caused a significant rise in the mitochondrial lipid peroxidation (LPO), protein carbonyl (PC) content and superoxide radical generation. It also affected the mitochondrial thiol profile. Pre-treatment of mice with lipoic acid (35 mg/kg) markedly lowered mitochondrial LPO, PC content and superoxide radical generation. It also restored decreased enzymatic and non-enzymatic antioxidants of mitochondria. It is suggested that lipoic acid has a potential role in suppressing MTX-induced mitochondrial toxicity, and it affords protection either by reversing the decline of antioxidants or by the directly scavenging the free radicals.
Tabassum
Heena
H
Immunotoxicology Laboratory, Department of Medical Elementology and Toxicology, Jamia Hamdard (Hamdard University), New Delhi 110062, India.
Parvez
Suhel
S
Pasha
Syed Tazeen
ST
Banerjee
Basu Dev
BD
Raisuddin
Sheikh
S
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D005493:Folic Acid Antagonists / Q000633:toxicity*; D005609:Free Radicals / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D066298:In Vitro Techniques; D050356:Lipid Metabolism / Q000187:drug effects; D008727:Methotrexate / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D051379:Mice; D008930:Mitochondria, Liver / Q000187:drug effects*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D050050:Protein Carbonylation / Q000187:drug effects; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D008063:Thioctic Acid / Q000494:pharmacology*
D005493:Folic Acid Antagonists; D005609:Free Radicals; D013438:Sulfhydryl Compounds; D017392:Thiobarbituric Acid Reactive Substances; D013481:Superoxides; D008063:Thioctic Acid; D004247:DNA; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D005978:Glutathione; D008727:Methotrexate