Modulation of induced cardiocytotoxicity and genotoxicity of doxorubicin in rat by L-carnitine

ABSTRACT

Doxorubicin [DOX] is an anthracycline antibiotic with broad-spectrum antitumor activity. Its effectiveness has been limited by the occurrence of dose related myocardial and bone marrow toxicity. L-carnitine is tested in this study to evaluate its protective effect against DOX induced cytotoxicity and genotoxicity. Four groups of adult female rats, each of 15 animals were used; one is used as control receiving 0.5 ml of saline, the other groups received either DOX [3mg/kg], L-carnitine [100mg/kg] or a combination of the two drugs. The treatment was continued i.p. every other day for two weeks. Five animals of each group were injected with 0.2ml of colchicine 2 h before sacrifice, which took place 24 h after the last treatment. Cardiotoxicity was assessed by measuring the serum levels of lactic acid dehydrogenase [LDH], creatine phosphokinase [CPK], glutamic oxaloacetic transaminase [GOT]. Reduced glutathione [GSH], malonaldehyde [MDA] and mitochondrial palmitoyl Co-A and octanoate oxidation were also, determined in cardiac tissue homogenate. The femurs were removed and bone marrow was processed for the preparation of metaphase chromosomes and determination of mitotic activity. DOX significantly increased LDH, CPK, GOT and MDA and significantly decreased GSH and palmitoyl Co-A. Administration of L-carnitine one hour before DOX treatment caused significant recovery for the serum enzymes LDH, CPK, GOT, and MDA, GSH and palmitoyl Co-A. Cytogenetic analysis showed that DOX increased the incidence of chromosomal aberration 18.4% in bone marrow cells and inhibited mitosis to about 50% of its normal rate. Administration of L-carnitine one hour before treatment with DOX significantly decreased the incidence of chromosomal aberrations [14.8%] and increased mitotic activity [10.4]. The results suggest that the cardiotoxicity and genotoxicity induced by DOX took place via a number of possible mechanisms. The results obtained suggest that L-carnitine could be used together with DOX as an adjuvant therapy