Inhibition of protein synthesis in mice by ochratoxin A and its prevention by phenylalanine

Creppy, E. E.; Röschenthaler, R.; Dirheimer, G.

doi:10.1016/0278-6915(84)90170-4

Cited by 101 publications

(41 citation statements)

References 10 publications

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“…Several studies have demonstrated that OTA inhibits protein synthesis via inhibition of phenylalanyl-tRNA synthetase interfering with peptide elongation (Creppy et al 1984(Creppy et al , 1990Dirheimer and Creppy 1991). Interestingly, in our data set, phenylalanyl-tRNA synthetase, alpha subunit (Farsa) was decreased in all studies (Table 4B).…”

Section: Discussionmentioning

confidence: 97%

Transcriptomic alterations induced by Ochratoxin A in rat and human renal proximal tubular in vitro models and comparison to a rat in vivo model

et al. 2011

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Ochratoxin A (OTA) is a widely studied compound due to its role in renal toxicity and carcinogenicity. However, there is still no consensus on the exact mechanisms of toxicity or carcinogenicity. In the current study, we analysed the effect of OTA on three human renal proximal tubular models (human primary, RPTEC/TERT1 and HK-2 cells) and two rat renal proximal tubular models (rat primary and NRK-52E cells). Global transcriptomics analysis at two exposure times was performed to generate a set of 756 OTA sensitive genes. This gene set was then compared in more detail across all models and additionally to a rat in vivo renal cortex model. The results demonstrate a well-conserved response across all models. OTA resulted in deregulation of a number of pathways including cytoskeleton, nucleosome regulation, translation, transcription, ubiquitination and cell cycle pathways. Interestingly, the oxidative stress activated Nrf2 pathway was not enriched. These results point to an epigenetic action of OTA, perhaps initiated by actin binding as the actin remodelling gene, advillin was the highest up-regulated in all models. The largest model differences were observed between the human and the rat in vitro models. However, since the human in vitro models were more similar to the rat in vivo model, it is more likely that these differences are model-specific rather than species-specific per se. This study demonstrates the usefulness of in vitro cell culture models combined with transcriptomic analysis for the investigation of mechanisms of toxicity and carcinogenicity. In addition, these results provide further evidence supporting a non-genotoxic mechanism of OTA-induced carcinogenicity.

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Section: Discussionmentioning

confidence: 97%

Transcriptomic alterations induced by Ochratoxin A in rat and human renal proximal tubular in vitro models and comparison to a rat in vivo model

et al. 2011

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“…OA seems to produce its toxic effects by one of three major mechanisms: (a) inhibition of phenylalanine metabolizing enzymes, thereby affecting DNA, RNA and protein synthesis (Meisner & Meisner, 1981;Meisner et al, 1983;Creppy et al, 1984); (b) promotion of lipid peroxidation by complexing iron, facilitating reduction of iron . Hasinoff et al (1990) reported that an iron complex of OA produced the extremely toxic hydroxyl radical in the presence of the NADPHÁcytochrome P-450 reductase system and this radical was partly responsible for OA toxicity; or (c) inhibition of mitochondrial ATP production by acting as a competitive inhibitor of carrier proteins located in the inner mitochondrial membrane (Meisner & Chan, 1974;Wei et al, 1985).…”

Section: Discussionmentioning

confidence: 99%

Individual and combined effects of ochratoxin A andSalmonella entericaserovar Gallinarum infection on pathological changes in broiler chickens

et al. 2008

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“…As the organic anion carrier is a very complex terti ary active transport system [14] we cannot state which possible action of OTA leads to its altered kinetics. The OTA-induced inhibition of protein synthesis [30] or the interaction of OTA with mitochondrial respiration [31] may be involved in the reduced capacity of PAH secretion.…”

Section: Effect O F Subchronic Application O F Ota On Pah Handlingmentioning

confidence: 99%

The Role of the Proximal Tubule in Ochratoxin A Nephrotoxicity in vivo: Toxodynamic and Toxokinetic Aspects

Gekle¹,

Silbernagl²

1994

Kidney Blood Press Res

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The proximal tubule of the kidney is regarded the main intrarenal target of the nephrotoxin Ochratoxin A (OTA). To gain further insight into the importance of the proximal tubule we investigated renal p-aminohippurate (PAH), inorganic phosphate (P), amino acid (AA) and OTA handling in male Wistar rats. The acute application of OTA (1.2 mg/kg) did not affect the renal handling of any of the substances investigated in contrast to the acute effect of OTA on ‘postproximal parts of the nephron. Application of OTA (0.5 mg/(kg·day)) over 6 days resulted in a dramatic decrease of the transport maximum of PAH (reduction to 15% of control) and to an increase of the apparent affinity of PAH to the organic anion transporter. Absolute excretion of P was not increased, whereas - due to the reduced GFR - the fractional excretion (FE) increased (to 180% of control). FE of the AA was not affected by OTA. Free-flow micropuncture experiments performed in L-homoarginine-loaded rats - to unmask possible small alterations of the amino acid transport kinetics - revealed that the proximal tubular transport of amino acids is not impaired by OTA. Subchronic exposure of the animals to OTA reduced the excretion of the mycotoxin itself to about 15% of controls. We conclude that the proximal tubule is not the main but one important intrarenal target of subchronically applied OTA. Furthermore, the action of OTA on the proximal tubule leads to decreased capacity to eliminate OTA possibly resulting in a self-enhancing effect

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Inhibition of protein synthesis in mice by ochratoxin A and its prevention by phenylalanine

Cited by 101 publications

References 10 publications

Transcriptomic alterations induced by Ochratoxin A in rat and human renal proximal tubular in vitro models and comparison to a rat in vivo model

Transcriptomic alterations induced by Ochratoxin A in rat and human renal proximal tubular in vitro models and comparison to a rat in vivo model

Individual and combined effects of ochratoxin A andSalmonella entericaserovar Gallinarum infection on pathological changes in broiler chickens

The Role of the Proximal Tubule in Ochratoxin A Nephrotoxicity in vivo: Toxodynamic and Toxokinetic Aspects

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