Biochemical determinants of adriamycin® toxicity in mouse liver, heart and intestine

Odom, A.Louis; Hatwig, Christopher A.; Stanley, J. Steven; Benson, Ann M.

doi:10.1016/0006-2952(92)90250-m

Cited by 74 publications

(41 citation statements)

References 20 publications

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“…ROS were shown to induce p21 gene expression by an unknown mechanism that may involve p53 (123, 369,422). This underscores the importance of ROS scavenging mechanisms in the proliferative phase of cellular responses.…”

Section: Induction Of the Cell Cycle Inhibitor P21 By Rosmentioning

confidence: 96%

Free Radicals in the Physiological Control of Cell Function

Dröge

2002

Physiological Reviews

8,372

5,836

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At high concentrations, free radicals and radical-derived, nonradical reactive species are hazardous for living organisms and damage all major cellular constituents. At moderate concentrations, however, nitric oxide (NO), superoxide anion, and related reactive oxygen species (ROS) play an important role as regulatory mediators in signaling processes. Many of the ROS-mediated responses actually protect the cells against oxidative stress and reestablish “redox homeostasis.” Higher organisms, however, have evolved the use of NO and ROS also as signaling molecules for other physiological functions. These include regulation of vascular tone, monitoring of oxygen tension in the control of ventilation and erythropoietin production, and signal transduction from membrane receptors in various physiological processes. NO and ROS are typically generated in these cases by tightly regulated enzymes such as NO synthase (NOS) and NAD(P)H oxidase isoforms, respectively. In a given signaling protein, oxidative attack induces either a loss of function, a gain of function, or a switch to a different function. Excessive amounts of ROS may arise either from excessive stimulation of NAD(P)H oxidases or from less well-regulated sources such as the mitochondrial electron-transport chain. In mitochondria, ROS are generated as undesirable side products of the oxidative energy metabolism. An excessive and/or sustained increase in ROS production has been implicated in the pathogenesis of cancer, diabetes mellitus, atherosclerosis, neurodegenerative diseases, rheumatoid arthritis, ischemia/reperfusion injury, obstructive sleep apnea, and other diseases. In addition, free radicals have been implicated in the mechanism of senescence. That the process of aging may result, at least in part, from radical-mediated oxidative damage was proposed more than 40 years ago by Harman ( J Gerontol 11: 298–300, 1956). There is growing evidence that aging involves, in addition, progressive changes in free radical-mediated regulatory processes that result in altered gene expression.

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Section: Induction Of the Cell Cycle Inhibitor P21 By Rosmentioning

confidence: 96%

Free Radicals in the Physiological Control of Cell Function

Dröge

2002

Physiological Reviews

8,372

5,836

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“…Lipid peroxidation is a major cardiotoxic indicator of doxorubicin, particularly under the conditions of acute exposure. It has been found that doxorubicin more selectively induces this oxidative damage to the heart relative to other organs such as the liver in mice (38). We have determined the lipid peroxide levels in the heart induced by doxorubicin as a function of time (days).…”

Section: Table I Enzyme Activities Of Sod Gsh Peroxidase and Gsh Rementioning

confidence: 99%

Suppression of Doxorubicin Cardiotoxicity by Overexpression of Catalase in the Heart of Transgenic Mice

Kang

Chen

Epstein

1996

Journal of Biological Chemistry

280

211

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Weak antioxidant capacity, particularly low catalase activity in the heart, may be a factor responsible for the high sensitivity of this organ to doxorubicin-induced oxidative damage. To test this hypothesis, a heart-specific promoter was used to drive the expression of murine catalase cDNA in transgenic mice. Fifteen healthy transgenic mouse lines were produced. Cardiac catalase activity was constitutively overexpressed in both atrium and ventricle, ranging from 2-to 630-fold higher than normal. This enzyme activity was not altered in liver, kidneys, lungs, and skeletal muscles. Other antioxidant components, including glutathione, glutathione peroxidase, glutathione reductase, metallothionein, and superoxide dismutase, were not altered in the catalaseoverexpressing heart. Mice (7 weeks old) from several transgenic lines and from nontransgenic controls were treated intraperitoneally with doxorubicin at a single dose of 20 mg/kg and sacrificed on the 4th day after treatment. As compared to normal controls, transgenic lines expressing catalase activity 60-or 100-fold higher than normal exhibited a significant resistance to doxorubicin-induced cardiac lipid peroxidation, elevation of serum creatine phosphokinase, and functional changes in the isolated atrium. Interestingly, 200-fold or greater elevation of catalase activity did not provide protection. The results provide direct evidence for the role of catalase in doxorubicin cardiotoxic responses.

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“…Mammalian cells can prevent oxidative stress: reactive oxygen species and lipid hydroperoxides are enzymatically or non-enzymatically detoxified by oxidizing GSH to GSSG, and the GSSG, that is formed, is immediately reduced back to GSH by GSH reductase by using NADPH (Reed & Beatty 1980). It has been demonstrated that redox cycling of adriamycin occurs in liver, heart and intestine (Odom et al 1992). The susceptibility of tissue to the oxidative stress depends on the capacity of GSH-dependent protective machinery.…”

Section: Discussionmentioning

confidence: 99%

Lipid Peroxidation Induced by Adriamycin in Linolenic Acid‐Loaded Cultured Hepatocytes

Furuno

Suetsugu

Shimomichi

et al. 1998

Pharmacology & Toxicology

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Addition of more than 10 pM of adriamycin to cultured rat hepatocytes loaded with a-linolenic acid (linolenic acid-loaded hepatocytes) caused marked lipid peroxidation as measured by an accumulation of malondialdehyde during a 9 hr incubation. After addition of 50 pM of adriamycin to linolenic acid-loaded hepatocytes, malondialdehyde accumulation significantly increased at 3 hr, followed by cellular reduced glutathione decrease and lactate dehydrogenase leakage after 6 hr. Inhibition of adriamycin-induced lipid peroxidation by addition of N,N'-diphenyl-p-phenylenediamine or atocopherol, both lipid radical scavengers, or deferoxamine, which is a Fe ion chelator, prevented both glutathione decrease and lactate dehydrogenase leakage, indicating that lipid peroxidation caused cellular damage to linolenic acid-loaded hepatocytes exposed to adriamycin. The effect of SKF 525-A, which is a cytochrome P450 inhibitor, on adriamycininduced lipid peroxidation and on 7-ethoxycoumarin 0-deethylase activity was determined by 6 hr incubation of linolenic acid-loaded cells. Addition of SKF 525-A suppressed adriamycin-induced lipid peroxidation comparably with its 7-ethoxycoumarin 0-deethylase inhibitory activity. These results suggest that cytochrome P450 contributes to the one-electron bioreduction of adriamycin into its semiquinone radical in rat hepatocytes.

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Biochemical determinants of adriamycin® toxicity in mouse liver, heart and intestine

Cited by 74 publications

References 20 publications

Free Radicals in the Physiological Control of Cell Function

Free Radicals in the Physiological Control of Cell Function

Suppression of Doxorubicin Cardiotoxicity by Overexpression of Catalase in the Heart of Transgenic Mice

Lipid Peroxidation Induced by Adriamycin in Linolenic Acid‐Loaded Cultured Hepatocytes

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