A possible role for membrane lipid peroxidation in anthracycline nephrotoxicity

doi:10.1016/0006-2952(86)90713-6

Biochemical Pharmacology

Volume 35, Issue 23, 1 December 1986, Pages 4327-4335

https://doi.org/10.1016/0006-2952(86)90713-6 Get rights and content

Abstract

Adriamycin causes both glomerular and tubular lesions in kidney, which can be severe enough to progress to irreversible renal failure. This drug-caused nephrotoxicity may result from the metabolic reductive activation of Adriamycin to a semiquinone free radical intermediate by oxidoreductive enzymes such as NADPH-cytochrome P-450 reductase and NADH-dehydrogenase. The drug semiquinone, in turn, autoxidizes and efficiently generates highly reactive and toxic oxyradicals. We report here that the reductive activation of Adriamycin markedly enhanced both NADPH- and NADH-dependent kidney microsomal membrane lipid peroxidation, measured as malonaldehyde by the thiobarbituric acid method. Adriamycin-enhanced kidney microsomal lipid peroxidation was diminished by the inclusion of the oxyradical scavengers, superoxide dismutase and 1,3-dimethylurea, and by the chelating agents, EDTA and diethylenetriamine-pentaacetic acid (DETPAC), implicating an obligatory role for reactive oxygen species and metal ions in the peroxidation mechanism. Furthermore, the inclusion of exogenous ferric and ferrous iron salts more than doubled Adriamycin-stimulated peroxidation. Lipid peroxidation was prevented by the sulfhydryl-reacting agent, p-chloromercuribenzenesulfonic acid, by omitting NAD(P)H, or by heat-inactivating the kidney microsomes, indicating the requirement for active pyridine-nucleotide linked enzymes. Several analogs of Adriamycin as well as mitomycin C, drugs which are capable of oxidation-reduction cycling, greatly increased NADPH-dependent kidney microsomal peroxidation. Carminomycin and 4-demethoxydaunorubicin were noteworthy in this respect because they were three to four times as potent as Adriamycin. In isolated kidney mitochondria, Adriamycin promoted a 12-fold increase in NADH-supported (NADH-dehydrogenase-dependent) peroxidation. These observations clearly indicate that anthracyclines enhance oxyradical-mediated membrane lipid peroxidation in vitro, and suggest that peroxidation-caused damage to kidney endoplasmic reticulum and mitochondrial membranes in vivo could contribute to the development of anthracycline-caused nephrotoxicity.

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Citation Excerpt :
The therapeutic vitality of these antineoplastic agents, such as daunorubicin and doxorubicin, has been compromised by increased resistance and dose-dependent toxicities including severe nephrotoxicity.87 The mechanism of anthracycline associated nephrotoxicity is not clearly understood but it has been proposed that anthracycline metabolism may induce the mitochondrial toxicities such as membrane disruption, impairment of calcium homeostasis, induction of free radical, lipid peroxidation and release of cytochrome C that may contribute toward apoptosis or necrosis of glomerular and tubular cells.88–90 Montilla et al. first time reported the melatonin potential to ameliorate the doxorubicin (adriamycin) induced nephrotoxicity in terms of oxidative stress and hyperlipidemia.91
Drug-induced nephrotoxicity is a frequent adverse event that can lead to acute or chronic kidney disease and increase the healthcare expenditure. It has high morbidity and mortality incidence in 40–70% of renal injuries and accounts for 66% cases of renal failure in elderly population.
Amelioration of drug-induced nephrotoxicity has been long soughed to improve the effectiveness of therapeutic drugs. This study was conducted to review the melatonin potential to prevent the pathogenesis of nephrotoxicity induced by important nephrotoxic drugs.
We analyzed the relevant studies indexed in Pubmed, Medline, Scielo and Web of science to explain the molecular improvements following melatonin co-administration with special attention to oxidative stress, inflammation and apoptosis as key players of drug-induced nephrotoxicity.
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The comprehensive nephroprotection and safer profile suggests the melatonin to be a useful adjunct to improve the safety of nephrotoxic drugs.
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^☆: These results were presented in part at the Annual Meeting of the American Society for Pharmacology and Experimental Therapeutics, August 7–11, 1983, in Philadelphia, PA.

^‡: Present address: Department of Environmental Health Sciences, Division of Experimental Pathology and Toxicology, Johns Hopkins School of Hygiene and Public Health, Baltimore, MD 21205.

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A possible role for membrane lipid peroxidation in anthracycline nephrotoxicity☆

Abstract

Int. J. Radiat. Oncol. Biol. Phys.

Cancer Chemother. Rep.

Biochem. biophys. Res. Commun.

Biochem. Pharmac.

Biochem. Pharmac.

Biochim. biophys. Acta

Chem. Biol. Interact.

Biochem. Pharmac.

J. biol. Chem.

J. biol. Chem.

J. biol. Chem.

J. biol. Chem.

Kidney Int.

Archs Biochem. Biophys.

J. inorg. Biochem.

Biochem. biophys. Res. Commun.

J. biol. Chem.

J. biol. Chem.

Biochem. Pharmac.

Lab. Invest.

Lab. Invest.

Am. J. vet. Res.

Archs Intern. Med.

Lab. Invest.

Am. J. vet. Res.

J. natn. Cancer Inst.

J. clin. Invest.

Cancer Treat. Rep.

Drug chem. Toxic.

Gann

Cancer Res.

Cancer, N.Y.

J. Pharmac. exp. Ther.