Increased serum and cardiac acyl-carnitine/free carnitine ratio during development of doxorubicin-induced cardiotoxicity

This study has been initiated to investigate whether cumulative doxorubicin [DOX] therapy alters serum and cardiac carnitine levels and if so, whether these alterations should be viewed as a mechanism and /or as an index during development of DOX-induced cardiotoxicity. To achieve the ultimate goal of this study, a total of 40 adult male Wistar albino rats were divided into 4 groups. In the first group, animals were injected intraperitoneally [I. P.] with normal saline [0.5 ml/200 gm body weight] and served as a normal control. Animals in the second to the fourth groups were injected every other day with DOX [3 mg/kg, I.P.], to obtain treatments with cumulative doses of 6 mg/kg [group 2], 12 mg/kg [group 3] and 18 mg/kg [group 4]. At 24 hours after receiving the last dose of DOX, animals were sacrificed serum as well as hearts were isolated and analyzed. DOX induced a significant and dose-dependent increase in serum creatine phosphokinase isoenzyme [CK-MB], lactate dehydrogenase [LDH], acyl-carnitine [AC]/free carnitine [FC] ratio and a significant decrease in serum free FC. In cardiac tissues, DOX induced a significant 46% and 63% decrease in FC after cumulative doses of 12 and 18 mg/kg, respectively. In contrast to FC, DOX induced a significant 70% and 81% increase in AC after cumulative doses of 12 and 18 mg/kg, respectively. Moreover, DOX treatment showed significant and dose-dependent decrease in adenosine triphosphate [ATP] level in cardiac tissues. In conclusion, data from this study suggest that: [1] Decreased myocardial carnitine level should be viewed as a mechanism during development of DOX cardiotoxicity, and [2] the parallel increase of serum AC/FC ratio and cardiotoxicity enzymatic indices, may point to the possible consideration of AC/FC ratio as a marker during development of DOX cardiotoxicity

Effects of trichloroacetate, water chlorination by-product, on liver peroxisomes and antioxidant status in rats and mice

Seven groups of each of male Fischer 344 rats and B6C3F1 mice were provided with drinking water containing distilled water 0.05 g/L trichloroacetate [TCA], 0.5 g/L TCA, 1.0 g/L TCA, 4.5 g/L TCA; distilled water + vitamin E and 4.5 g/L TCA + vitamin E, respectively, for 30 days. Liver palmitoyl Co-A oxidase [PCOA] and glycolate oxidase were estimated as peroxisomal enzymes. In addition, the liver content of water-soluble antioxidants, antioxidant enzymes and alpha- tocopherol were measured. These results demonstrated that the mouse is more sensitive than the rat with respect to the enhancement of liver peroxisome proliferation by TCA. A condition of oxidative stress produced by TCA exposure in drinking water was conducted. The possible role of oxidative damage in the hepatic carcinogenicity of TCA may be involved

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

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