CARDIOTOXIC EFFECTS OF THE ANTINEOPLASTIC DOXORUBICIN IN A MODEL OF METABOLIC SYNDROME: OXIDATIVE STRESS AND TRANSPORTERS EXPRESSION IN THE HEART.

ABSTRACT The aim of the present work was to examine whether metabolic syndrome-like conditions in rats with fructose (F) overload modify the cardiotoxic effects induced by doxorubicin (DOX) and whether the treatment altered the expression of P-gp, BCRP and OCTN transporters in the heart. Male Sprague-Dawley rats received either tap water (C, control group; n=16) or water with F 10% w/v (n=16) during eight weeks. Three days before sacrifice, the animals received a single dose of DOX (6 mg/kg, ip, md) (C-DOX and F-DOX groups) or vehicle (VEH; ISS 1ml/kg BW; ip) (C-VEH and F-VEH groups) (n=8 per group). F overload enhanced thiobarbituric acid-reactive substances (TBARS) levels in the left ventricle, and DOX injection further increased those values. DOX did not alter TBARS production in C animals. DOX caused a decrease of 30% in the ejection fraction and a nearly 40% reduction in the fractional shortening in F animals, but not in C rats. Cardiac tissue levels of P-gp decreased by about 30% in F rats compared to the C groups. DOX did not modify cardiac P-gp expression. BCRP and OCTN1/2/3 protein levels did not change with either F or DOX. It is suggested that DOX could cause greater cardiotoxicity in rats receiving F, probably due to enhanced cardiac lipid peroxidation and lower expression of cardiac P-gp. These results support the hypothesis that the cardiotoxicity of DOX could be increased under metabolic syndrome-like conditions or in other health disorders that involve cardiovascular risk factors.