Metabolic Syndrome: Synergistic Risks for Doxorubicin-Induced Cardiotoxicity.
Metabolic Syndrome: Synergistic Risks for Doxorubicin-Induced Cardiotoxicity.
复制标题
DOI：
10.1097/fjc.0000000000001140
复制
发表时间：
2021-12-01
影响因子：
3
通讯作者：
Gomez-Sanchez EP
中科院分区：
文献类型：
--
作者：
Gomez-Sanchez EP
The use of doxorubicin (Adriamycin), a widely used antineoplastic drug effective against several types of cancer, is limited by its cardiac toxicity, particularly in patients with concurrent risk factors for heart disease, including metabolic syndrome (MetS). Ogonowski et al report that a single moderate dose of doxorubicin produced significant cardiac toxicity in a rat dietary fructose model of MetS compared to rats on a standard diet. 1 Before the administration of doxorubicin, the fructose-fed rats had hypertension, significantly elevated plasma triglycerides, and increased indices of lipid peroxidation and oxidative stress, but lower P-glycoprotein, expression and superoxide dismutase activity in their hearts. The fructose-fed rats were not obese, nor did they have significant hyperglycemia or echocardiographic evidence of cardiac dysfunction. However 3 days after doxorubicin treatment, ejection fraction and fractional shortening were significantly decreased only in the MetS rats and cardiac lipid peroxidation was further increased. 1 Although the definition of MetS varies, hypertension, dyslipidemia, and increased inflammation and oxidative stress observed in these fructose-fed rats are criteria common to all. 2 The relevance of this study is augmented by the use of a moderate model of MetS and dose of doxorubicin reflective of many patients who develop cardiotoxicity despite being relatively healthy before initiating doxorubicin treatment.P-glycoprotein, also called multiple drug-resistant protein1 and ATP-binding cassette (ABC) transporter 1, is responsible for the active transport of endogenous and exogenous compounds, including doxorubicin, out of cells. P-glycoprotein measured by western blot was decreased by 30% in the hearts of the fructose-fed rat before challenge with doxorubicin and was not altered after its administration (Ogonowski et al). The effect of inflammation on the expression of P-glycoprotein or its gene, ABCB1 (multiple drug resistant protein1), depends on the cell type. 3, 4 It is suppressed in hepatocytes and vascular and intestinal endothelial cells forming barriers of the brain and gut, yet increased in renal tubules. In a mouse model of lipopolysaccharide inflammation, the excretion of doxorubicin was decreased in the bile, but increased in the urine. 5 The cardiotoxicity of doxorubicin is attributed primarily to its main metabolite doxorubicinol, which is ineffective as an antineoplastic agent. As circulating doxorubicinol does not cross the vascular endothelial barrier, its accumulation and toxicity in cardiomyocytes depends on enzymatic formation from doxorubicin within the heart. 6 The short-chain alcohol dehydrogenases 11b-hydroxysteroid dehydrogenase type 1 (11bHSD1) and carbonyl reductase1 are the primary enzymes responsible for catalyzing the formation of doxorubicinol from doxorubicin. 7 Although most often associated with the reduction of the inactive steroids cortisone and 11-dehydrocorticosterone to the endogenous glucocorticoids cortisol and corticosterone, 11bHSD1 is an important reductase of diverse carbonyl-bearing xenobiotics, including doxorubicin, 7 for entry into phase 1
