Iron chelation as a possible mechanism for aspirin-induced malondialdehyde production by mouse liver microsomes and mitochondria.

Schwarz, Kathleen B.; Arey, Brian J.; Tolman, Keith G.; Mahanty, Srikrishna

doi:10.1172/jci113289

Cited by 20 publications

(6 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, Steer et al 13 affirmed that aspirin both in vivo and in vitro protects LDL (low-density lipoproteins) against subsequent oxidative modification, thereby providing an additional mechanism whereby aspirin may protect against atherosclerosis. Schwarz et al 12 reported that ASA intensifies MDA (malondialdehyde) production in hepatic microsomes and mitochondria. In our study we noticed that the TBARS concentration significantly increased in all investigated tissues of animals exposed both to F and ASA.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Oxidative stress parameters in rats exposed to fluoride and caffeine

Inkielewicz‐Stępniak

Czarnowski

2010

Food and Chemical Toxicology

View full text Add to dashboard Cite

SUMMARY:The action of fluoride (F) and aspirin (acetylsalicylic acid, ASA) administered separately and together on oxidative stress parameters and on F excretion in rats was studied over a period of six weeks. Thirty adult male Wistar rats were divided into five equal groups of six each: (I) controls receiving tap water; (II) controls receiving intragastrically 1 mL of tap water (once a day); (III) animals receiving 25 mg F/L in their drinking water; (IV) animals receiving 35 mg ASA/kg bw/ day; (V) animals receiving 25 mg F/L in drinking water and 35 mg ASA/kg bw/day. In rats treated only with fluoride the F excretion in urine significantly increased in an exposure time-dependent manner and decreased both in rats treated with ASA and co-exposed to ASA and F. In animals treated with ASA alone, the activity of glutathione peroxidase (GPx) and the concentrations of glutathione (GSH) and thiobarbituric acid reactive substances (TBARS) increased in brain, liver and blood, whereas the activity of catalase (CAT) decreased in liver and erythrocytes, but increased in liver. In rats exposed to F alone the concentration of GSH and the activities of GPx and CAT decreased, whereas the concentration of TBARS significantly increased in liver, brain, kidney and blood. In rats co-exposed to F and ASA, the concentrations of GSH and TBARS and the activities of GPx and CAT (except in liver) were higher than in animals receiving only F.

show abstract

Section: Discussionmentioning

confidence: 99%

“…[10][11] At present there are several scientific reports about the effect of ASA on antioxidant potential. [12][13][14] However, there does not appear to be any information available in the literature about interactions between F and ASA in soft tissues.…”

Section: Introductionmentioning

confidence: 99%

Oxidative stress parameters in rats exposed to fluoride and caffeine

Inkielewicz‐Stępniak

Czarnowski

2010

Food and Chemical Toxicology

View full text Add to dashboard Cite

show abstract

“…The formation, isolation, and characterization of an aspirin iron complex have also been reported during studies of oxidative damage to the liver mitochondria by aspirin, where the iron complex of aspirin was implicated in the toxicity [173]. In contrast, a mechanism of antioxidant action through the chelation of intracellular low-molecular-weight iron was proposed in cell studies, where aspirin has been shown to protect endothelial cells from oxidative stress damage caused by hydrogen peroxide [174]. Similarly, chelation of iron by aspirin has been suggested to be related to its antioxidant activity in the improvement of cataracts in diabetic models and other models of oxidative damage [175,176].…”

Section: Interactions Of Aspirin (Acetylsalicylic Acid) and Its Glucu...mentioning

confidence: 89%

The Puzzle of Aspirin and Iron Deficiency: The Vital Missing Link of the Iron-Chelating Metabolites

Kontoghiorghes

2024

IJMS

View full text Add to dashboard Cite

Acetylsalicylic acid or aspirin is the most commonly used drug in the world and is taken daily by millions of people. There is increasing evidence that chronic administration of low-dose aspirin of about 75–100 mg/day can cause iron deficiency anaemia (IDA) in the absence of major gastric bleeding; this is found in a large number of about 20% otherwise healthy elderly (>65 years) individuals. The mechanisms of the cause of IDA in this category of individuals are still largely unknown. Evidence is presented suggesting that a likely cause of IDA in this category of aspirin users is the chelation activity and increased excretion of iron caused by aspirin chelating metabolites (ACMs). It is estimated that 90% of oral aspirin is metabolized into about 70% of the ACMs salicyluric acid, salicylic acid, 2,5-dihydroxybenzoic acid, and 2,3-dihydroxybenzoic acid. All ACMs have a high affinity for binding iron and ability to mobilize iron from different iron pools, causing an overall net increase in iron excretion and altering iron balance. Interestingly, 2,3-dihydroxybenzoic acid has been previously tested in iron-loaded thalassaemia patients, leading to substantial increases in iron excretion. The daily administration of low-dose aspirin for long-term periods is likely to enhance the overall iron excretion in small increments each time due to the combined iron mobilization effect of the ACM. In particular, IDA is likely to occur mainly in populations such as elderly vegetarian adults with meals low in iron content. Furthermore, IDA may be exacerbated by the combinations of ACM with other dietary components, which can prevent iron absorption and enhance iron excretion. Overall, aspirin is acting as a chelating pro-drug similar to dexrazoxane, and the ACM as combination chelation therapy. Iron balance, pharmacological, and other studies on the interaction of iron and aspirin, as well as ACM, are likely to shed more light on the mechanism of IDA. Similar mechanisms of iron chelation through ACM may also be implicated in patient improvements observed in cancer, neurodegenerative, and other disease categories when treated long-term with daily aspirin. In particular, the role of aspirin and ACM in iron metabolism and free radical pathology includes ferroptosis, and may identify other missing links in the therapeutic effects of aspirin in many more diseases. It is suggested that aspirin is the first non-chelating drug described to cause IDA through its ACM metabolites. The therapeutic, pharmacological, toxicological and other implications of aspirin are incomplete without taking into consideration the iron binding and other effects of the ACM.

show abstract

“…This finding implies that it is the acetyl group within acetylsalicylic acid that confers the capacity to activate ferritin synthesis and that all other inhibitors of cyclooxygenase tested, including nonacetylated salicylate, do not fulfill the structural requirements necessary to activate ferritin translation. Aspirin has been demonstrated to specifically interact with and show affinity toward iron or iron complexes, 6,26 and it is therefore conceivable that aspirin accelerates dissociation of the ferritin repressor protein from ferritin mRNA, thus allowing ferritin translation. Clearly, more research is needed in order to further analyze the molecular mechanisms by which aspirin exerts its ferritin-inducing effect.…”

Section: Discussionmentioning

confidence: 99%

Aspirin Increases Ferritin Synthesis in Endothelial Cells

Oberle

Polte

Abate

et al. 1998

Circulation Research

View full text Add to dashboard Cite

Aspirin has recently been shown to increase endothelial resistance to oxidative damage. However, the mechanism underlying aspirin-induced cytoprotection is still unknown. Using cultured cells, the present study investigates the effect of aspirin on the expression of ferritin, a cytoprotective protein that sequesters free cytosolic iron, the main catalyst of oxygen radical formation. In bovine pulmonary artery endothelial cells, aspirin at low antithrombotic concentrations (0.03 to 0.3 mmol/L) induced the synthesis of ferritin protein in a time-and concentration-dependent fashion up to 5-fold over basal levels, whereas ferritin H (heavy chain) mRNA remained unaltered. Aspirin-induced cytoprotection from hydrogen peroxide toxicity was mimicked by exogenous iron-free apoferritin but not iron-loaded ferritin, demonstrating the antioxidant function of newly synthesized ferritin under these conditions. Ferritin induction by aspirin was specific in that other nonsteroidal anti-inflammatory drugs such as salicylic acid, indomethacin, or diclofenac failed to alter ferritin protein levels. Aspirin-induced ferritin synthesis was abrogated in the presence of the iron chelator desferrioxamine, pointing to an interaction of aspirin with iron-responsive activation of ferritin translation. Together, our results suggest induction of ferritin as a novel mechanism by which aspirin may prevent endothelial injury in cardiovascular disease, eg, during atherogenesis. (Circ Res. 1998;82:1016-1020.) Key Words: aspirin ferritin endothelial cell gene expression antioxidant defense mechanism A spirin is known to reduce the incidence of thrombotic occlusive events such as myocardial infarction and stroke. 1 This effect is considered to be due to the platelet inhibitory action of aspirin, which results from irreversible inhibition of platelet cyclooxygenase activity and thromboxane formation. 2 Thromboxane is a potent agonist and crucial mediator of vascular smooth muscle contraction and platelet aggregation. 3 Recently, however, a more direct effect of aspirin on the integrity of the vascular wall has been reported in studies involving the antioxidant properties of aspirin and the capacity of aspirin to protect endothelial cells from the deleterious effects of hydrogen peroxide and, in particular, from iron-dependent oxygen radical formation. 4-6 The mechanism responsible for the observed aspirin-induced endothelial protection is unknown. From the data published by Podhaisky et al, 6 it appears that cytoprotection by aspirin is a long-term effect that occurs after several hours of pretreatment. Therefore, a possible mechanism might be the induction of genes that protect cells from damage by reactive oxygen species. In recent studies, the induction of ferritin has been shown to provide marked antioxidant cellular protection by rapidly sequestering free cytosolic iron, the crucial catalyst of oxygen-centered radical formation via the Fenton reaction in biological systems. 7,8 Thus, ferritin, which until then was thought to function merely as ...

show abstract

Iron chelation as a possible mechanism for aspirin-induced malondialdehyde production by mouse liver microsomes and mitochondria.

Cited by 20 publications

References 31 publications

Oxidative stress parameters in rats exposed to fluoride and caffeine

Oxidative stress parameters in rats exposed to fluoride and caffeine

The Puzzle of Aspirin and Iron Deficiency: The Vital Missing Link of the Iron-Chelating Metabolites

Aspirin Increases Ferritin Synthesis in Endothelial Cells

Contact Info

Product

Resources

About