Toxicity of Doxorubicin (Dox) to different experimental organ systems

The Efficacy of Amifostine against Multiple-Dose Doxorubicin-Induced Toxicity in Rats

“…An already weakened heart is unable to increase cardiac output, so further increase in the intravascular volume and venous pressure leads to additional fluid release into the tissues. On the other hand, hepatic oedema contributes to the increased permeability of the capillary wall that has already arisen due to the damage under the influence of DOX [9,15,32,59]. Such intensive disorders of water metabolism lead to the formation of small or large vacuoles in the cytoplasm of hepatocytes, as result of extreme enlargement of mitochondria and vesiculation of endoplasmic reticulum.…”

“…Although the exact mechanism of DOX-induced hepatotoxicity and nephrotoxicity remains unknown, it is believed that the toxic effects are mediated by free radical formation, iron-dependent oxidative damage of biological macromolecules, membrane lipid peroxidation, and protein oxidation [15,19,24,25,26,66,67]. Moreover, nitric oxide synthase may be responsible for the reductive activation of DOX to its free radical semiquinone form, and the subsequent oxygen radical-mediated cellular damage.…”

“…There are numerous experimental models concerning these subjects, which showed DOX-induced bone marrow toxicity, cardiotoxicity, hepatotoxicity, nephrotoxicity, and toxic effects on the GI tract (GIT), reproductive system, and nervous system [4,9,10,11,12,13,14,15]. DOX acts as a strong inhibitor of DNA duplication and transcription, with the most obvious consequences on tissues with strong proliferative potential, such as bone marrow, GIT, and the reproductive system.…”

“…On the other hand, DOX, by virtue of its quinone group, generates free radicals in vitro and in vivo, which is significantly stimulated by its interaction with iron. Moreover, oxidative stress, apoptosis, and inflammation can be taken as possible mechanisms of DOX multiple-organ toxicity, such as cardiotoxicity on the first place [5,12,15,16,17,18,19]. …”

“…In that case, irreversible alterations lead to hepatocyte apoptosis or necrosis, and intensive increase of hepatic enzymes in the blood, primarily alanine aminotransferase (ALT) and aspartate aminotransferase (AST) [9]. It is also believed that the DOX-induced nephrotoxicity may be mediated through free radical formation, iron-dependent oxidative damage of biological macromolecules, membrane lipid peroxidation, and protein oxidation [15,19,26]. Experimental animals that received DOX developed focal segmental glomerulosclerosis, followed by massive proteinuria, which is a certain nephrotic syndrome severity marker [10,27].…”