The mycotoxin ochratoxin A is a substrate for phenylalanine hydroxylase in isolated rat hepatocytes and in vivo

Creppy, E. E.; Chakor, Kheira; Fisher, Michael J.; Dirheimer, G.

doi:10.1007/bf01972987

Cited by 58 publications

(24 citation statements)

References 32 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: 99%

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: 99%

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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“…He also showed that OTA inhibited intramitochondri:a.1 phosph:a.te transport, resulting in dcteriOTalion of the mitochondria. The f:a.ilure of OTA 10 deplete ATP in Tat hepatocyles 10 observed by Creppy et al (1990), and the ability of 011(, which is non-loxic. 10 inhibit mitochondrial respiration more effectively than OTA (Moore and Truelove, 1970) would suggest that mitochondrial effects probably did not contribute to the toxic effects of OTA.…”

Section: 18mentioning

confidence: 93%

Effect of cytochrome P450 induction on the metabolism and toxicity of ochratoxin A

Omar

Gelboin

Rahimtula

1996

Biochemical Pharmacology

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The role of cytochrome P-450 in me stimulation of lipid peroxidation induccd by thc mycotoxin ochratoxin A (OTA) has been investigated. Purified cytochrome P-450 (liB I) could effectively replace EDTA in stimulating lipid pefOxidation in a reconstituted system l'Onsisling of phospholipid vesicles, NADPH-cYlochrome P-450rcduc!ase, FeJ+, EDTA and NADPll, suggesting that it could mediate the transfer of electrons from NADPH to foc3,. Microsomcs isolated from liven of cobalt protoporphyrin IX-treated rllts (in which cytochrome P-450 Wll" depletedj underwent OTA-dependent lipid peroxidation much more slowly tlmn control microsomes.The role of cytochrome P-450 in OTA met.1bolism was also investigated. To dClermine which cytochrome P·450 isoforms are involved in the metabolism ofOTA, we used different cytochrome P-450 inducers to induce the major isofonns of cytochrome 1'-450 in lhe rm liver.Microsomes from these livers were used to investigate their effect on OTA metabolism.Pretreatment ofmts with pregnenolone -16c(·carbonitrile (peN), phenobarbit.ll (PB), 3-ll1cthyl cholanthrene (3MC), and isosafrole (ISF) greatly induced 4(R)-4-0H-OTA fonmllion; 4(5)-4-011-OTA fonnation was also induced after pretreatment with PB, PCN, 3MC and ISr:. INII pretreaunem primarily induced me 4(5) isomer formation, The fonnation of the 4(R) .md 4 (5) isomeri showed significant differences with respect to pH optima, effect of antioKidants ami iron chelators, The 4(R) isomer fonnation showed a pH optimum of 6.0 using microsornes from rJIs treated with 3MC and ISF, and 6.5 using mierosomes from rats treated with PI] :tnd peN and Wi!S not inhibited by antioxidants or iron chelators. In contmst, both the 4(5) isomer fonmllion and lipid pcroxidation showed a pH optimum of 7.0 -7,5 and both activities were highly sensitive to inhibition by antioxidants and iron ehelators. Lipid peroxides were no: involved in the 4(5) isomer fonnation since addition of linoleic acid hydroperoxidc to microsomcs did not give rise 10 the 4(5) isomer, Cytochrome P-450 appeared to be essenlial since other hemoprolcins such as horseradish peroxidase and hemoglobin were ineffective in metabolizing OTA. Microsomes from rats pretreated with Co-protoporphyrin IX resulted in no metabolil,rn of ochratoxin A. 7-Ethoxy-and 7-pentoxyresorufin assays showed specificity towards cytochromes P-450 induced by 3MC (fA I/lA2) and PB (IIBI) respectively. Also, metyrapone (inhibitor of cytochrome P·450 IIBt) preferentially inhibited OTA mel1bolism by microsomes from rats treated with PB, and I(-naphthoflavone (inhibitor of cytochrome P-450 IAI/lA2) preferentially inhibited OTA metabolism by microwmes from 3MC and ISF treated rats_ Monoclonal antibodies (MAbs) 1-7-1 (against P-450 lA 1/lA2) and 2-66-3 (against P-450 liB I) showed preferential inhibition ofOTA metabolism by microsomes from 3MC and PB treated rats respectively.Excretion of renal enzymes in urine is a sensitive non-invasive index of renal dam:lge.Therefore. we examined the effect of cytochrome P-450 induction on the...

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“…It has a number of toxic effects that may be the result of inhibition of ATP synthesis; enhanced lipid peroxidation (LPO) and inhibition of protein synthesis (Marquardt and Frohich, 1992). Ochratoxin A inhibits protein synthesis by competition with phenylalanine in the aminoacylation reaction of phenylalanine-tRNA (Bunge et al, 1978) and phenylalanine hydroxylase activity (Creppy et al, 1990), which could lead to impairment of the synthesis of DOPA, dopamine and derived compounds. Ochratoxin A also induces oxidative damage by enhancing LPO (Rahimtula et al, 1988;Omar et al, 1991).…”

Section: Introductionmentioning

confidence: 99%

Protective role of melatonin in ochratoxin a toxicity in rat heart and lung

Okutan

Aydin

Özçelik

2004

J of Applied Toxicology

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Ochratoxin A (OTA) is a mycotoxin produced by different fungi. The most pronounced adverse effect of OTA is hepatonephrotoxicity. Melatonin (MEL) has an antioxidant effect and has free-radical scavenger properties. The effects of OTA on heart and lung tissue and possible ameliorating effects of MEL were investigated in rats. Twenty-four rats were allocated to three groups (each with eight rats): control; OTA-treated group (OTA dose 289 microg kg(-1) per day); and OTA + MEL-treated group (MEL dose 10 mg kg(-1) per day). After 30 days of treatment, the histopathological changes in the heart and lung of all groups were examined. Compared with the control rats, myocardial tissue of rats treated with OTA showed extensive cytoplasmic vacuole formation, necrosis of the myocytes, dissolution of the nucleus, clumped fibres, fibrillolysis, swollen myocardial fibres, small haemorrhagic areas and hyperaemic vessels (P <0.05). In addition, lungs of rats treated with OTA showed alveolar congestion, alveolar cell hyperplasia, prominent alveolar septal vessels, variable intensity loss of alveolar architecture, intraparenchymal inflammatory infiltration, intraparenchymal hyperaemic vessels, respiratory epithelial proliferation, perivascular and peribronchial inflammation, pneumonic infiltration, distorted appearance of lung parenchyma and emphysematous areas (P <0.05). In comparison with the OTA groups, the ameliorating effects of MEL in the lung damage parameters were on alveolar cell hyperplasia, prominent alveolar septal vessels, variable intensity loss of alveolar architecture, intraparenchymal inflammatory infiltration, perivascular inflammatory inflammation, distorted appearance of lung parenchyma and focal emphysematous areas in lung (P <0.05). Melatonin also significantly reduced myocardial damage in most of the parameters: extensive cytoplasmic vacuole formation, necrosis of the myocytes, clumped fibres, fibrillolysis, small haemorrhagic areas and hypaeremic vessels in heart (P <0.05). On the other hand, MEL did not lower the degree of damage in lung and heart to the level of the control rats, except for the parameters of the interstitial oedema and small haemorrhagic areas only in myocardial tissue. Histopathological findings showed that OTA induced damage in heart and lung and MEL treatment significantly reduced the degree of damage.

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The mycotoxin ochratoxin A is a substrate for phenylalanine hydroxylase in isolated rat hepatocytes and in vivo

Cited by 58 publications

References 32 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

Effect of cytochrome P450 induction on the metabolism and toxicity of ochratoxin A

Protective role of melatonin in ochratoxin a toxicity in rat heart and lung

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