Lipid peroxidation as a possible cause of ochratoxin a toxicity

Rahimtula, Anver D.; Béréziat, Jean‐Claude; Bussacchini-Griot, Valeria; Bartsch, Helmut

doi:10.1016/0006-2952(88)90662-4

Cited by 159 publications

(40 citation statements)

References 28 publications

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“…Changes in renal enzyme activities were also observed in these cotreatment experiments [30,31]. The hypothesis of oxidative stress being involved in OTA-mediated genetic damage is further strengthened by evidence from studies revealing OTA-dependent lipid peroxidation and free radical formation in mammalian cells and other systems as well as in rats [32][33][34][35]. Decreased concentrations of vitamin E in plasma of rats [30], and of glutathione in liver of mice, in primary hepatocytes and in CV-1 cells have also been reported after OTA treatment [22,36,37].…”

mentioning

confidence: 66%

“…One plausible mechanism of OTA-induced carcinogenesis that can be envisaged to be operative is DNA damage resulting from oxidative stress [e.g., 22,30,31,[34][35][36][37]61]. Several in vivo studies have shown that repeated dosing of rats with OTA (0.25 mg/kg bw per day for 4 wk, or 0.12 mg/kg bw per day for 8 wk) leads to increased levels of reactive oxygen species in liver, kidney, and plasma.…”

Section: Discussionmentioning

confidence: 99%

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Ochratoxin A induces oxidative DNA damage in liver and kidney after oral dosing to rats

Kamp¹,

Eisenbrand

Janzowski

et al. 2005

Mol. Nutr. Food Res.

105

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The nephrotoxic/carcinogenic mycotoxin ochratoxin A (OTA) occurs as a contaminant in food and feed and may be linked to human endemic Balkan nephropathy. The mechanism of OTA-derived carcinogenicity is still under debate, since reactive metabolites of OTA and DNA adducts have not been unambiguously identified. Oxidative DNA damage, however, has been observed in vitro after incubation of mammalian cells with OTA. In this study, we investigated whether OTA induces oxidative DNA damage in vivo as well. Male F344 rats were dosed with 0, 0.03, 0.1, 0.3 mg/kg bw per day OTA for 4 wk (gavage, 7 days/wk, five animals per dose group). Subsequently, oxidative DNA damage was determined in liver and kidney by the comet assay (single cell gel electrophoresis) with/without use of the repair enzyme formamido-pyrimidine-DNA-glycosylase (FPG). The administration of OTA had no effect on basic DNA damage (determined without FPG); however, OTA-mediated oxidative damage was detected with FPG treatment in kidney and liver DNA of all dose groups. Since the doses were in a range that had caused kidney tumors in a 2-year carcinogenicity study with rats, the oxidative DNA damage induced by OTA may help to explain its mechanism of carcinogenicity. For the selective induction of tumors in the kidney, increased oxidative stress in connection with severe cytotoxicity and increased cell proliferation might represent driving factors.

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mentioning

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Ochratoxin A induces oxidative DNA damage in liver and kidney after oral dosing to rats

Kamp¹,

Eisenbrand

Janzowski

et al. 2005

Mol. Nutr. Food Res.

105

View full text Add to dashboard Cite

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“…The mechanisms observed in these studies -e. g., direct and unspecific inhibition of macromolecule synthesis [1], DNA adduct formation [77], lipid peroxidation [78], oxidative damage [3], uncoupling of mitochondria [76] -occur only at very high (experimental) levels of exposure and thus represent a so-called "primary nonspecific" action. These high doses certainly can lead to general and unspecific cell perturbations, cell transformation, and subsequent tumor formation.…”

Section: Which Mechanisms Mediate Ota-toxicity?mentioning

confidence: 99%

Ochratoxin A at nanomolar concentrations: A signal modulator in renal cells

Gekle¹,

Sauvant

Schwerdt

2005

Mol. Nutr. Food Res.

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Ochratoxin A (OTA) is a ubiquitous fungal metabolite with nephrotoxic, carcinogenic, and apoptotic potential. Toxicokinetics make the kidney the primary target organ for OTA. Due to its widespread occurrence in improperly stored foodstuff the complete and safe avoidance of OTA for humans is impossible. There are several reports showing a significant correlation between OTA exposure and certain forms of nephropathies. At nanomolar concentrations OTA leads to specific changes of function and phenotype in renal cells. The toxin interacts with certain cellular "key-molecules" (e. g., mitogen-activated protein (MAP) kinases, Ca2+), thereby disturbing cellular signalling and regulation events as well as mitochondrial function. Moreover, OTA has the ability to modulate physiological signals (e. g., angiotensin II or TNFalpha) and thereby influences cell function and cell growth and may even stable re-program the cells (e. g., altered distribution of chromosomes). This review concentrates on the effects of OTA in the nanomolar range and its interactions with cellular signalling networks in different renal cells proposing OTA to act as a signal modulator.

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“…It has been hypothesized by Chu et al (1972) that the toxicity of OA is directly related to the degree that the C-8 phenolic hydroxyl group is ionized. Rahimtula et al (1988) hypothesized that an iron complex of the C-8 phenolate ion and not the undissociated form of OA facilitated the reversible oxidationreduction of iron and that this complex was involved in enhanced lipid peroxidation. However, structure-activity studies in our laboratory with different analogs of OA on B. brevis, HeLa cells, and the mouse indicated that there was not a clear relationship between the degree of ionization of the C-8 phenolate group of the different analogs of OA at physiological pH values and their corresponding toxic effects in different biological systems (Xiao et al, 1996).…”

Section: ϩmentioning

confidence: 99%

“…Based on the current literature, the toxicity of OA may be the result of three major effects: 1) inhibition of ATP synthesis; 2) inhibition of protein synthesis; and 3) enhanced lipid peroxidation (Marquardt and Frohlich, 1992;Röschenthaler et al, 1984). Rahimtula et al (1988) showed that OA, when added to rat liver microsomes, enhanced the rate of NADPH or ascorbate-dependent lipid peroxidation as measured by malondialdehyde formation. In vivo administration of OA to rats also resulted in enhanced lipid peroxidation.…”

mentioning

confidence: 99%

Free Radical Generation as Induced by Ochratoxin A and Its Analogs in Bacteria (Bacillus brevis)

Hoehler¹,

Marquardt

McIntosh

et al. 1996

Journal of Biological Chemistry

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Lipid peroxidation is considered as one of the manifestations of cellular damage in the toxicity of ochratoxin A (OA). OA; its three natural analogs, OB, OC, and O␣; and four synthetic analogs, d-OA, the ethylamide of OA (OE-OA), O-methylated OA (OM-OA), and the lactoneopened OA (OP-OA) were used to study free radical generation in bacteria with Bacillus brevis as a model system. The uptake of the different ochratoxins by B. brevis varied substantially depending on the molecular structures. Electron paramagnetic resonance spectroscopy using ␣-(4-pyridyl-1-oxide)-N-tert-butyl nitrone as a spin trapping agent showed an enhanced free radical generation due to the addition of OA and most of the analogs. The EPR signals could be further enhanced by the addition of Ca 2؉ , a calcium ionophore and an ATPase uncoupler, whereas they were eliminated by incubating the growing cells with vitamin E. The spin adduct hyperfine splitting constants indicate the presence of ␣-hydroxyethyl radicals resulting from generated hydroxyl radicals, which are trapped by ␣-(4-pyridyl-1-oxide)-N-tertbutyl nitrone. The results further suggest that OA induces free radical production in this model system by enhancing the permeability of the cellular membrane to Ca 2؉ .

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Lipid peroxidation as a possible cause of ochratoxin a toxicity

Cited by 159 publications

References 28 publications

Ochratoxin A induces oxidative DNA damage in liver and kidney after oral dosing to rats

Ochratoxin A induces oxidative DNA damage in liver and kidney after oral dosing to rats

Ochratoxin A at nanomolar concentrations: A signal modulator in renal cells

Free Radical Generation as Induced by Ochratoxin A and Its Analogs in Bacteria (Bacillus brevis)

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