Role of iron in the potentiation of anthracycline cardiotoxicity: Identification of heart cell mitochondria as a major site of iron-anthracycline interaction

Link, Gabriela; Tirosh, Régine; Pinson, A; Hershko, Chaim

doi:10.1016/s0022-2143(96)90095-5

Cited by 129 publications

(95 citation statements)

References 28 publications

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“…Figures 4,5,and 6 show the effect of fatty acid metabolism on ADR-treated rats with or without CARN administration. ADR caused significant elevations of long-chain fatty acids such as palmitic (C16:0), linoleic (C18:2), oleic (C18:1), and stearic acids (C18:0) after injection of ADR (Fig.…”

Section: Effect Of Adr On Lipidmentioning

confidence: 99%

“…The precise mechanism of this pathogenesis has not been completely defined (4,5). A number of different mechanisms have been proposed for the cardiotoxic effect of ADR (6 -13), such as its interaction with nucleic acid and/or with nuclear components, disruption of cardiac-specific effects of gene expression, and low antioxidant defense in tissue such as the heart.…”

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confidence: 99%

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Serum Lipid and Fatty Acid Profiles in Adriamycin-Treated Rats after Administration of L-Carnitine

Hong

Kim

Yoon³

2002

Pediatr Res

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Cardiomyopathy induced by Adriamycin (ADR) is a cause of congestive heart failure. Recently, it has been suggested that ADR inhibits the carnitine palmitoyltransferase system (CPT I) and consequently the transport of long-chain fatty acids across mitochondrial membranes. This study was devised to ascertain how ADR affects serum lipid and fatty acid metabolism in rats given ADR with and without L-carnitine supplementation. Male Sprague-Dawley rats were divided into four groups. The first group was the control. The second group was given intraperitoneal injections of ADR (5 mg/kg) twice a week over a period of 2 wk. The third group received the same dose of ADR plus L-carnitine (200 mg/kg). The fourth group was injected with L-carnitine only. Serum lipids (total cholesterol, triglyceride, HDL cholesterol, and LDL cholesterol) and fatty acid levels were determined on the first, eighth, and 15th d after injection of ADR. ADR caused an increase of serum total cholesterol, triglyceride, and LDL cholesterol compared with the control group. HDL cholesterol was similar between two groups. Similarly, total fatty acids, especially C16-C18 fatty acids, were significantly elevated after injection of ADR. Striking reduction in these substances was observed when L-carnitine was added (p Ͻ 0.05). This study is the first report regarding the reversal effect of L-carnitine in connection with FFA profiles (C6-C18) in the serum of ADRinduced cardiomyopathic rats. This study also supports the view that ADR causes cardiomyopathy because it interferes with fatty acid metabolism, and we hypothesize that there is a possible protective effect of L-carnitine. (Pediatr Res 51: 249-255, 2002) Abbreviations ADR, Adriamycin CARN, L-carnitine CPT, carnitine palmitoyltransferase FFA, free fatty acid ADR (doxorubicin) is an anthracycline antibiotic and has major clinical significance because of its broad-spectrum antitumor activity. Several studies show a cumulative dosedependent and irreversible cardiotoxicity that limits its usefulness as a broad-spectrum anticancer drug (1, 2). One major chronic side effect is the development of cardiomyopathy and ultimately congestive heart failure known as ADR cardiomyopathy (3).The precise mechanism of this pathogenesis has not been completely defined (4, 5). A number of different mechanisms have been proposed for the cardiotoxic effect of ADR (6 -13), such as its interaction with nucleic acid and/or with nuclear components, disruption of cardiac-specific effects of gene expression, and low antioxidant defense in tissue such as the heart. An abnormal fatty acid metabolism has been suggested by . Although alteration of fatty acid oxidation has been associated with ADR, the lack of understanding of fatty acid metabolism in this type of cardiotoxicity and other cardiomyopathies has led to conflicting results.Recently, it has been suggested that ADR may exert at least a part of its cardiotoxicity by inhibition of long-chain fatty acid oxidation in the heart (18). Because long-chain fatty acids are the major su...

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Section: Effect Of Adr On Lipidmentioning

confidence: 99%

mentioning

confidence: 99%

Serum Lipid and Fatty Acid Profiles in Adriamycin-Treated Rats after Administration of L-Carnitine

Hong

Kim

Yoon³

2002

Pediatr Res

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“…The precise mechanism for the pathogenesis in ADRinduced cardiomyopathy has not been elucidated (1,2). A number of different hypotheses have been proposed to account for the cardiotoxic effect of ADR.…”

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confidence: 99%

Effect of L-Carnitine Supplementation on Cardiac Carnitine Palmitoyltransferase Activities and Plasma Carnitine Concentrations in Adriamycin-Treated Rats

et al. 2003

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Adriamycin (ADR) inhibits the carnitine palmitoyl transferase (CPT) system and consequently the transport of longchain fatty acids across mitochondrial membranes. L-Carnitine (CARN) plays a major role in fatty acid oxidation by translocating activated long-chain fatty acids into the matrix of mitochondria. CARN has been shown to be of benefit in certain cardiac conditions including cardiomyopathy and myocardial infarction. This study was devised to investigate the effect of CARN on altered CPT I and CPT II activity in the cardiomyopathy associated with ADR therapy. We also assessed the effect of CARN on the plasma free, total, and acylcarnitine concentrations. Four groups, each consisting of four male Sprague-Dawley rats, were studied: group 1(n ϭ 4) was not given either ADR or CARN; group 2 (n ϭ 4) was given ADR (15 and 20 mg/kg, respectively, cumulative dose) by i.p. injections for 1 and 2 wk; group 3 (n ϭ 4) was given the same dose of ADR with CARN (200 mg/kg); and group 4 (n ϭ 4) was given CARN (200 mg/kg). The activities of CPT I and CPT II in heart were significantly decreased in the ADR-treated rats (p Ͻ 0.05) in a dose-dependent manner. The reduced activities of CPT I and CPT II, inhibited by ADR, were not normalized by supplementation with CARN (p Ͻ 0.05). In rats supplemented with CARN alone, the activities of CPT I and CPT II were elevated approximately 50% above those of the control rats (p Ͻ 0.05). ADR treatment resulted in elevation of plasma free and total CARN concentrations (p Ͻ 0.05). Supplementation with CARN did not effect the increased plasma CARN concentrations resulting from ADR treatment (p Ͻ 0.05). This study supports the concept that ADR toxicity results from the inhibition of both CPT I and CPT II activities and that one of the causes of ADR-induced cardiomyopathy is a result of globally impaired fatty acid oxidation. The precise mechanism for the pathogenesis in ADRinduced cardiomyopathy has not been elucidated (1, 2). A number of different hypotheses have been proposed to account for the cardiotoxic effect of ADR. These include the production of free radical species (3, 4), leading to lipid peroxidation of cardiac microsomal membranes (5), the differential accumulation and retention of positively charged ADR as a result of high negative membrane potential (6), an interaction with nucleic acid or nuclear components (7), and disruption of a cardiacspecific program of gene expression (8). Increased myocardial lipid accumulation and plasma lipid levels are usually associated with ADR-induced cardiomyopathy (9).It has been suggested that ADR may exert at least part of its cardiotoxicity by inhibition of fatty acid oxidation in the heart (10 -14). Impaired cardiac fatty acid oxidation is usually associated with diastolic dysfunction (15), cardiomyopathy, and congestive heart failure as a result of a deficiency in energy supply and possible accumulation of toxic intermediates of fatty acid oxidation in cardiac tissues (16).Two CPT activities exist within mitochondria; CPT I and CPT II are l...

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“…(11,12) Iron once within the cell is bound to ferritin and transported to lysosomes for degradation and long-term storage. (13) If storage capacity is exceeded, free intracellular iron is able to be highly reactive (7) and cause multiple toxic cellular effects, including, impaired Na-K-ATPase activity, increased lysosomal fragility and impaired mitochondrial respiratory chain activity (14,15,16) and the potential to worsen any Correspondence: J. Malcolm Walker A full version of this article, including a complete list of references will be published in Heart and will be available for viewing at "Heart.BMJ.com" ischaemia induced reperfusion injury. (17,18) The eventual consequence is heart failure.…”

Section: Iron Toxicitymentioning

confidence: 99%

Thalassaemia Major and the Heart

Walker

2013

Thalassemia Reports

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Role of iron in the potentiation of anthracycline cardiotoxicity: Identification of heart cell mitochondria as a major site of iron-anthracycline interaction

Cited by 129 publications

References 28 publications

Serum Lipid and Fatty Acid Profiles in Adriamycin-Treated Rats after Administration of L-Carnitine

Serum Lipid and Fatty Acid Profiles in Adriamycin-Treated Rats after Administration of L-Carnitine

Effect of L-Carnitine Supplementation on Cardiac Carnitine Palmitoyltransferase Activities and Plasma Carnitine Concentrations in Adriamycin-Treated Rats

Thalassaemia Major and the Heart

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