An in vitro study of the ameliorative role of α-tocopherol on methotrexate-induced oxidative stress in rat heart mitochondria

Singh, Kanika; Malviya, Anant N.; Bhori, Mustansir; Marar, Thankamani

doi:10.1515/jbcpp-2012-0020

Cited by 11 publications

(7 citation statements)

References 33 publications

(23 reference statements)

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“…Interestingly, inhibition of mtFAO has been documented with several of these drugs, namely tamoxifen, raloxifene and NRTIs [3,28,93,94]. Moreover, drugs such as tamoxifen, methotrexate and NRTIs can inhibit MRC activity and favor oxidative stress [3,16,28,95,96]. However, for some of these compounds, aggravation of preexisting NAFLD could also be secondary to other mechanisms.…”

Section: Drug-induced Inhibition Of Mtfao and Aggravation Of Nafldmentioning

confidence: 99%

Drug-Induced Inhibition of Mitochondrial Fatty Acid Oxidation and Steatosis

et al. 2013

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Drug-induced inhibition of mitochondrial fatty acid b-oxidation (mtFAO) is a key mechanism whereby drugs can induce steatosis. The type and severity of this liver lesion is dependent on the residual mtFAO flux. Indeed, a severe inhibition of mtFAO leads to microvesicular steatosis, hypoglycemia and liver failure, which can be favored by genetic predispositions. In contrast, moderate impairment of mtFAO can cause macrovacuolar steatosis, which is by itself a benign lesion. In the long-term, however, macrovacuolar steatosis can progress with some drugs to steatohepatitis. Interestingly, drugs that are more likely to cause steatohepatitis are those impairing the mitochondrial respiratory chain (MRC) activity. Indeed, MRC impairment favors not only hepatic fat accretion but also oxidative stress and lipid peroxidation. Drugs inhibiting mtFAO could be more toxic in obese patients with preexisting nonalcoholic fatty liver disease (NAFLD) since higher mtFAO is a key metabolic adaptation to curb fat accretion during NAFLD.

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Section: Drug-induced Inhibition Of Mtfao and Aggravation Of Nafldmentioning

confidence: 99%

Drug-Induced Inhibition of Mitochondrial Fatty Acid Oxidation and Steatosis

et al. 2013

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“…In liver mitochondria, methotrexate promotes a significant rise in superoxide radical formation, as well as in lipid peroxidation, whereas the GSH levels are decreased [114]. Likewise, methotrexate significantly impairs the function of isolated heart mitochondria by promoting lipid peroxidation, mitochondrial swelling and by inhibiting complex I, II and IV activities [115].…”

Section: Folate Antagonistsmentioning

confidence: 99%

“…An in vitro study demonstrated that Vitamin E decreases the oxidative stress induced by methotrexate in rat heart mitochondria and thereby minimizes mitochondrial dysfunction [115]. Likewise, the administration of lipoic acid decreases oxidative stress induced by methotrexate, which affects liver mitochondrial function [114].…”

Section: A Mitochondrial Basis For Anticancer Drugs Combinations: a Pmentioning

confidence: 99%

Mitochondrial Dysfunction on the Toxic Effects of Anticancer Agents— From Lab Bench to Bedside

Ribeiro¹,

eSantos²,

Custódio³

2015

Toxicology Studies - Cells, Drugs and Environment

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“…Antioxidants have been widely used in the restoration of mitochondrial function [ 11 , 12 , 13 , 14 ]. Specifically, N -acetylcysteine (NAC), a prodrug for cysteine, is a well-known antioxidant and a precursor for the crucial intracellular antioxidant GSH [ 15 ] that protects against cellular damage caused by free radicals [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

N-Acetylcysteine Reverses the Mitochondrial Dysfunction Induced by Very Long-Chain Fatty Acids in Murine Oligodendrocyte Model of Adrenoleukodystrophy

et al. 2021

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The accumulation of saturated very long-chain fatty acids (VLCFA, ≥C22:0) due to peroxisomal impairment leads to oxidative stress and neurodegeneration in X-linked adrenoleukodystrophy (ALD). Among the neural supporting cells, myelin-producing oligodendrocytes are the most sensitive to the detrimental effect of VLCFA. Here, we characterized the mitochondrial dysfunction and cell death induced by VLFCA, and examined whether N-acetylcysteine (NAC), an antioxidant, prevents the cytotoxicity. We exposed murine oligodendrocytes (158 N) to hexacosanoic acid (C26:0, 1–100 µM) for 24 h and measured reactive oxygen species (ROS) and cell death. Low concentrations of C26:0 (≤25 µM) induced a mild effect on cell survival with no alterations in ROS or total glutathione (GSH) concentrations. However, analysis of the mitochondrial status of cells treated with C26:0 (25 µM) revealed depletion in mitochondrial GSH (mtGSH) and a decrease in the inner membrane potential. These results indicate that VLCFA disturbs the mitochondrial membrane potential causing ROS accumulation, oxidative stress, and cell death. We further tested whether NAC (500 µM) can prevent the mitochondria-specific effects of VLCFA in C26:0-treated oligodendrocytes. Our results demonstrate that NAC improves mtGSH levels and mitochondrial function in oligodendrocytes, indicating that it has potential use in the treatment of ALD and related disorders.

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An in vitro study of the ameliorative role of α-tocopherol on methotrexate-induced oxidative stress in rat heart mitochondria

Abstract: The present study suggests that vitamin E plays a vital role in suppressing MTX-induced mitochondrial toxicity, and affords protection either by reversing the decline of antioxidants or by direct scavenging of free radicals.

Cited by 11 publications

References 33 publications

Drug-Induced Inhibition of Mitochondrial Fatty Acid Oxidation and Steatosis

Drug-Induced Inhibition of Mitochondrial Fatty Acid Oxidation and Steatosis

Mitochondrial Dysfunction on the Toxic Effects of Anticancer Agents— From Lab Bench to Bedside

N-Acetylcysteine Reverses the Mitochondrial Dysfunction Induced by Very Long-Chain Fatty Acids in Murine Oligodendrocyte Model of Adrenoleukodystrophy

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