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PubMed1985

Metabolism of ochratoxin B and its possible effects upon the metabolism and toxicity of ochratoxin A in rats.

A metabolic product was formed from ochratoxin B by rat liver microsomal fractions in the presence of NADPH. It was isolated from the incubation mixture by extraction, thin-layer chromatography, high-pressure liquid chromatography, and crystallization. On the basis of mass and nuclear magnetic resonance spectroscopy, the structure is suggested to be 4-hydroxyochratoxin B. The Km for the formation of 4-hydroxyochratoxin B was determined, and the hydroxylation of ochratoxin A was not altered by the presence of ochratoxin B. Rats were given ochratoxin A or B, or a mixture of both intraperitoneally. The ratios of the three metabolites, ochratoxin A, (4R)-4-hydroxyochratoxin A, and ochratoxin alpha, excreted in the urine did not change in the presence of ochratoxin B. Ochratoxin B was metabolized to 4-hydroxyochratoxin B and ochratoxin beta, but in a different ratio than for the ochratoxin A metabolites. When given intraperitoneally, ochratoxin beta was excreted within 24 h. In rats treated with ochratoxin A alone, the food intake was reduced by 50%, and histologically severe lesions, degeneration, and necrosis were observed in the proximal tubules. When ochratoxin A and B given in combination, the animals were clinically unaffected and histologically there was only slight damage of proximal tubules. These observations indicate that ochratoxin B considerably reduces the toxic effects of ochratoxin A.

Animals↗
PubMed2001

Ochratoxin A-induced tumor formation: is there a role of reactive ochratoxin A metabolites?

Ochratoxin A is a nephrotoxic and tumorigenic mycotoxin which contaminates a variety of food items, resulting in chronic human exposure. Biotransformation reactions have been implicated in the tumorigenicity of ochratoxin A. The biotransformation of ochratoxin A by cytochromes P450 and other mammalian enzymes was investigated to optimize conditions for bacterial mutagenicity testing. Metabolite formation was assessed by HPLC with UV and fluorescence detection and by LC/MS/MS. When ochratoxin A was incubated with liver microsomes from rats and mice, formation of 4R- and 4S-hydroxyochratoxin A was observed at very low rates. However, oxidation of ochratoxin A was not observed using kidney microsomes from rats and mice. Significantly higher rates of oxidation were seen in liver microsomes from rats pretreated with 3-methylcholanthrene and dexamethasone. Other reported or postulated that ochratoxin A-metabolites were not formed in detectable concentrations. Human cytochromes P450 (3A4, 1A2, and 2C9-1 Supersomes((R))) also showed very low activity with ochratoxin A (<60 fmole/min x pmol P450). Other enzyme systems used to study possible biotransformation of ochratoxin A were rat and human liver and kidney S-9 fortified with NADPH and glutathione, semipurified glutathione S-transferases, horseradish peroxidase, and soybean lipoxygenase; none of these resulted in detectable biotransformation of ochratoxin A. Using rat liver microsomes with high activity for ochratoxin A oxidation and the other enzyme systems to activate ochratoxin A for mutagenicity testing in the Ames test, mutagenicity was not observed in Salmonella typhimurium TA 100 and TA 2638. The obtained results suggest that oxidative biotransformation of ochratoxin A occurs at low rates, is catalyzed by cytochromes P450, and is unlikely to form reactive intermediates capable of binding to DNA.

Animals↗
PubMed1992

Synthesis of 14C-ochratoxin A and 14C-ochratoxin B and a comparative study of their distribution in rats using whole body autoradiography.

Methods for preparation of labelled ochratoxin A and B are described. The method for preparation of labelled ochratoxin B involves the synthesis of the azide of ochratoxin beta via the mixed anhydride and subsequent conjugation to labelled phenylalanine to yield 14C-ochratoxin B. The labelled ochratoxins were injected into male Wistar rats and after different survival times they were sacrificed and subjected to whole body autoradiography. The distribution pattern of ochratoxin A in the rat did not differ from that earlier registered for mouse. The previously known, high susceptibility of rats (and not mice) to ochratoxin A-induced cancer could thus not be explained by an accumulation of the toxin in specific cells or organs. The distribution patterns of ochratoxin A and B were almost congruent--the only apparent difference being a much longer retention of the labelled ochratoxin A in the blood compared to ochratoxin B, which was much faster excreted. When analyzing tissue extracts for labelled metabolites only the extracts from the rats injected with ochratoxin B were found to contain easily detectable concentrations, while no metabolites of ochratoxin A were seen.

Animals↗
PubMed2005

Survey for co-occurrence of ochratoxin A and aflatoxin B1 in dried figs in Turkey by using a single laboratory-validated alkaline extraction method for ochratoxin A.

A survey was carried out to determine the co-occurrence of ochratoxin A and aflatoxin B1 in dried figs from Turkey. Samples from two seasons of crops (2003 and 2004) intended for export to the European Union and the 2004 crop obtained from the domestic Turkish market were analyzed. Affinity column cleanup methods were employed for determining separately ochratoxin A and aflatoxin B1, but for ochratoxin A an alkaline extraction procedure was employed (in contrast to the conventionally employed acidic extraction), which gave consistently higher toxin recovery. In-house validation of the ochratoxin A method gave a limit of detection of 0.15 ng/g and a limit of quantification of 0.5 ng/g with a repeatability of 5.8% in the range 5 to 10 ng/g (with a mean recovery of 94% for spiked samples). Positive results for ochratoxin A were confirmed by liquid chromatography-mass spectrometry. For the 2003 export figs (58 samples), 7 samples contained only aflatoxin B1, 2 samples contained only ochratoxin A, and 2 samples contained both toxins (with maximum concentrations of 35.1 ng/g for aflatoxin B1 and 13.0 ng/g for ochratoxin A). Similarly for the 2004 export figs (41 samples), 16 samples contained only aflatoxin B1, 4 samples contained only ochratoxin A, and 2 samples contained both toxins (with maximum concentrations of 20.6 ng/g for aflatoxin B1 and 26.3 ng/g for ochratoxin A). Of 20 retail samples of dried figs from Turkey, only one sample contained ochratoxin A (2.0 ng/g) and none were contaminated with aflatoxin B1. This survey revealed a 14 to 15% incidence of occurrence of ochratoxin A for 2 years, which is higher than previously reported.

Aflatoxin B1↗
PubMed1984

Conversion of ochratoxin C into ochratoxin A in vivo.

The conversion of ochratoxin C to ochratoxin A was studied in rats after oral and intravenous administration. The concentration of ochratoxin A in the blood as a function of time was the same after oral administration of equivalent amounts of either ochratoxin C or ochratoxin A. The maximum ochratoxin A concentrations were measured 60 min after administration. Given intravenously, ochratoxin C was also converted to ochratoxin A. Maximum concentrations were reached after 90 min. It is concluded that ochratoxin C is readily converted to ochratoxin A after both oral and intravenous administration. There is reason to believe that a comparable toxicity of the two toxins is based upon this conversion and that only interference with the biotransformation mechanisms may cause a difference in their toxicity.

Administration, Oral↗
PubMed2002

On ochratoxin A and fungal flora in Polish cereals from conventional and ecological farms - Part 1: occurrence of ochratoxin A and fungi in cereals in 1997.

Over 200 samples of Polish cereal grain from the 1997 harvest obtained from conventional and ecological farms were tested for the presence of ochratoxin A as well as for contamination by microscopic fungi. Ochratoxin A contamination of rye from ecological farms was over six times more frequent than that from conventional cultivation. The ochratoxin A content in wheat and barley samples from ecological farms was also higher. No wheat sample from conventional farms contained the mycotoxin. In the group of ecological farms, there were differences in the percentage of cereal samples containing ochratoxin A. The ochratoxin A levels ranged from 0.2 to 57 microg kg(-1). The mean concentration of ochratoxin A in investigated cereal grain was 5.7 microg kg(-1). From samples containing detectable amounts of ochratoxin A, fungi producing ochratoxin A under laboratory conditions were isolated. They were classified as belonging to the species Penicillium cyclopium, P. viridicatum, P. chrysogenum and also Aspergillus alliaceus, A. versicolor, A. glaucus and A. flavus. Penicillium strains - producers of ochratoxin A - were isolated from 93% of the samples; in 7% of samples, only Aspergillus strains producing this mycotoxin were noted. Rye samples mainly from one farm with an ecological type of cultivation and from one conventional farm were contaminated with both Aspergillus and Penicillium mycotoxigenic strains.

Aspergillus↗
PubMed2002

On ochratoxin A and fungal flora in Polish cereals from conventional and ecological farms. Part 2: occurrence of ochratoxin A and fungi in cereals in 1998.

Over 200 samples of Polish cereal grain from the 1998 harvest obtained from conventional and ecological farms were investigated for the presence of ochratoxin A and for contamination by microscopic fungi. The frequency of contamination of rye and barley grains from conventional and ecological farms was similar in most cases; it varied from nearly 5 to 12%, respectively, for both types of farming. However, in samples from ecological farms, higher maximum concentrations of ochratoxin A were observed (35 micro g kg(-1), overall range 1.4-35.3 micro g kg(-1)) for both cereals rye and barley in comparison with rye and barley from conventional farms (maximum levels of 8.8 and 9.7 micro g kg(-1), respectively). However, wheat grain from the conventional farms showed ochratoxin A concentrations in a very wide range from 0.6 to 1024 micro g kg(-1) and the average frequency of contaminated samples was about 48%. In contrast, in wheat samples from ecological farming, the presence of ochratoxin A ranged from 0.8 to 1.6 micro g kg(-1) (mean 1.2 micro g kg(-1)) and the frequency of contamination was 23%. From samples containing detectable amounts of ochratoxin A, fungi producing ochratoxin A under laboratory conditions were isolated. They were classified as belonging to the species Penicillium cyclopium, P. viridicatum, Aspergillus ochraceus group, A. glaucus and A. versicolor. Penicillium strains-species known to be producers of ochratoxin A-were isolated from 71% of the samples; in 28% of samples, only Aspergillus strains (species known to be producers of this mycotoxin) were noted. These results have been compared with those obtained in 1997.

Agriculture↗
PubMed1983

Effects of two metabolites of ochratoxin A, (4R)-4-hydroxyochratoxin A and ochratoxin alpha, on immune response in mice.

The metabolites of ochratoxin A, (4R)-4-hydroxyochratoxin A and ochratoxin alpha, were investigated for immunosuppressive properties in BALB/c mice. The standard plaque-counting technique for the estimation of antibody-producing spleen lymphocytes was used. (4R)-4-hydroxyochratoxin A was found to be an immunosuppressor almost as highly effective as ochratoxin A. Doses of 1 microgram of (4R)-4-hydroxyochratoxin A per kg administered to mice caused an 80% reduction in the number of cells producing immunoglobulin M (90% with ochratoxin A) and a 93% reduction in cells synthesizing immunoglobulin G (92% with ochratoxin A). Ochratoxin alpha, however, was ineffective. A possible mode of action is discussed.

Animals↗
PubMed1997

[Target proteins and mechanisms of ochratoxin toxicity. A contribution to the identification of potential ochratoxin antagonists]

Ochratoxins are mycotoxins released by moulds on grain, peanuts and vegetables. Toxicological investigations have shown that ochratoxin A displays nephrotoxic, genotoxic, teratogenic, cancerogenic and immunosuppressive effects. Increased blood levels observed in humans would seem to suggest a link to a kidney desease (Balcan Endemic Nephropaty) frequently observed in the Balkan countries. The adverse effects of ochratoxin A are mainly associated with its impact on phenylalanine-metabolizing enzymes. Based on the three-dimensional structure of phenylalanine-t-RNA-synthetase, its interactions with ochratoxins are analyzed as well as with Aspartam. In animal models, Aspartam has been shown to almost fully prevent toxic effects of ochratoxin A. The topology of the binding site of phenylalanine-t-RNA-synthetase would seem to be favorable towards a few affinity-enhancing modifications of the Aspartame molecule. A known molecular mechanism is a prerequisite for a systematic search of antagonizing substances for toxins. Based on a receptor structure, binding properties of such drugs can be identified and optimized using computer-aided drug design. Susequently, only the most potent candidate structures must be subjected to a determination of their biological activity, which can lead to a significant reduction of substances to be tested in vivo. Such experiments are particularly stressful as the animals must be intoxicated beforehand. The extent of an antagonistic impact on humans suffering from a chronical ochratoxin A intoxication must be subject of clinical studies.

Journal Article↗
PubMed1998

Kinetic profiles of ochratoxin A and ochratoxin alpha during in vitro incubation in buffered forestomach and abomasal contents from cows.

Pure ochratoxin A (OA) was added to buffered rumen fluid collected from fistulated cows and incubated under anaerobic conditions. The kinetic pattern of the disappearance of OA and the appearance of ochratoxin alpha (Oalpha) was principally the same with four diets fed to donor animals and with three donor animals. The concentration of OA declined to a very low or non-detectable level with half-lives at 0.17-1.84 h; its rate of disappearance was first order throughout. The concentration of Oalpha increased to a constant level under all conditions examined. The average amounts of Oalpha formed relative to the disappearance of OA were not different (p > 0.05) and ranged between 94 +/- 8 and 98 +/- 8 %. The rate of disappearance of OA differed (p < 0.001) between diets and animals. It was accelerated by increasing the content of concentrate in the diet. Ochratoxin alpha was not metabolized when added in pure form to buffered rumen fluid and incubated under the same conditions as OA. Pure OA was also added to buffered fluids from the forestomach and abomasum of a slaughtered cow. It disappeared exponentially in a mixture of fluids from the rumen and reticulum and in fluid from the omasum, with the average amounts of Oalpha formed relative to OA disappearance being 107 and 109 %, respectively. Ochratoxin A also was not metabolized in fluid from the abomasum. These studies demonstrate that OA is hydrolysed in the rumen via first order kinetics, diet and animal affect the rate of hydrolysis, OA is quantitatively converted to Oalpha and Oalpha is not degraded.

Abomasum↗
PubMed2005

Cloning a part of the ochratoxin A biosynthetic gene cluster of Penicillium nordicum and characterization of the ochratoxin polyketide synthase gene.

Penicillium nordicum is a fungal species able to produce high amounts of ochratoxin A. A 10kb genomic DNA fragment of P. nordicumn has been cloned which carries three long open reading frames. One open reading frame (otapksPN) has homology to fungal polyketide synthases. The second open reading frame (npsPN) has homology to non-ribosomal peptide synthetases and the third open reading frame (aspPN) has homology to fungal alkaline serine proteinases. The non-ribosomal peptide synthetase and the polyketide synthase are convergently transcribed. Interestingly, the polyketide synthase can be identified by PCR only in P. nordicum strains and not in the related species Penicillium verrucosum or in ochratoxigenic Aspergillus species, indicating that the ochratoxin polyketide synthases are different in the important ochratoxigenic species. In contrast, the non-ribosomal peptide synthetase can be identified in P. nordicum and P. verrucosum, but not in other species. An inactivation of the polyketide synthase resulted in strains with abolished capacity to produce ochratoxin A. Expression of the polyketide synthase correlates with ochratoxin A biosynthesis.

Amino Acid Sequence↗
PubMed2004

Development of a Real Time PCR system for detection of Penicillium nordicum and for monitoring ochratoxin A production in foods by targeting the ochratoxin polyketide synthase gene.

A 750 bp DNA fragment from the genome of Penicillium nordicum was isolated using degenerated primers for polyketide synthase genes. All analyzed P. nordicum strains possessed the fragment, whereas the closely related ochratoxinogenic P. verrucosum strains did not. The nucleotide sequence of the fragment has been determined. It shows homology to the pksL2 polyketide synthase gene from A. parasiticus. The deduced amino acid sequence of this fragment shows high homology to several other fungal polyketide synthases. An expression analysis of this gene by Reverse Transcription Real Time PCR demonstrates that this putative polyketide synthase gene (otapksPN) is highly induced under ochratoxin A producing conditions, but only to low levels under non-producing conditions. A Real Time PCR system based on the otapksPN sequence has been used to monitor growth and ochratoxin A production of P. nordicum in wheat. A strong correlation between the copy numbers of the otapksPN gene and the colony forming units (cfu) has been observed. In addition there was a strong congruence between otapksPN gene expression and ochratoxin A production in wheat. According to these results the fragment is obviously part of a polyketide synthase (otapksPN) which seems to be involved in the production of ochratoxin A.

Colony Count, Microbial↗
PubMed1977

Analysis of ochratoxin B alone and in the presence of ochratoxin A, using carboxypeptidase A.

A method is described for ochratoxin B analysis, which is adapted to the earlier described method of ochratoxin A analysis, using carboxypeptidase A (K. Hult and S. Gatenbeck, J. Assoc. Off. Anal. Chem. 59:128-129, 1976). The fluorescence spectra of ochratoxins A and B coincide too much to allow direct discrimination of the two compounds. A method using the differences in kinetic parameters of the enzymatic hydrolysis of the two compounds is suggested for the analysis of mixtures of the ochratoxins.

Carboxypeptidases↗
PubMed1997

Reduction of ochratoxin A toxicity by heat-induced epimerization. In vitro effects of ochratoxins on embryonic chick meningeal and other cell cultures.

The widespread contamination of food by mycotoxins may present a serious hazard to human and animal health. The present study was designed to determine the toxic potential of three structurally related ochratoxins: ochratoxin A (OTA), ochratoxin B (OTB) and the heat-induced 3S-epimer of OTA (3S-OTA) recently discovered in roasted coffee and human serum. The toxicity was determined using serum-free cell cultures of embryonic chick meningeal fibroblasts, taking the effects on mitochondrial and lysosomal activity and culture protein content as an index for toxicity. OTA, OTB and 3S-OTA were toxic. However, the concentration necessary to induce comparable effects were nearly 19- and 10-fold higher for OTB and 3S-OTA, respectively, than those for OTA. In a next step the sensitivity of serum-free cell cultures of embryonic chick neural retina and brain were compared in relation to meningeal cell cultures. In the present study, no indications for differences in sensitivity could be detected. Furthermore, our study suggest that the OTA-induced toxic effects are not due to the inhibition by OTA of phenylalanine-tRNA synthetase.

Animals↗
PubMed1998

Differences in neurotoxic effects of ochratoxin A, ochracin and ochratoxin-alpha in vitro.

The mycotoxin ochratoxin A (OTA) is a chlorinated dihydroisocoumarin derivative connected through an amide-bond to L-phenylalanine. In a previous study we could show that competition with L-phenylalanine-dependent processes does not play a role in OTA neurotoxicity. To test whether the isocoumarin part is responsible for the neurotoxic effects, we determined in the present study the effects of the hydrolysis product of OTA, ochratoxin-alpha (OTalpha), and of ochracin on embryonic chick brain cell cultures. In addition, we investigated the interaction between OTA and ochracin regarding the neurotoxic effects. We report here that OTalpha did not affect brain cell cultures at concentrations up to 15 microM. With the exception of a small (20%) but significant reduction in cell culture, cellular protein at concentrations above 0.3 microM, in our cell cultures' cell function, as defined by neutral red uptake and MTT-dehydrogenase activity, was only reduced by high OTalpha concentrations (1 mM). Addition of 0.1 microM OTA increased ochracin cytotoxicity as defined by latter parameters. No effects on cell culture NF68kD content could be detected. The results are discussed with regard to the existence of an OTA target interaction binding site.

Animals↗
PubMed1989

Influence of ochratoxin B on the ochratoxin A inhibition of phenylalanyl-tRNA formation in vitro and protein synthesis in hepatoma tissue culture cells.

Ochratoxin B (OTB), the dechloro-analogue of ochratoxin A (OTA), was studied separately and in combination with OTA on the aminoacylation of phenylalanine tRNA (tRNAPhe) catalysed by mice liver phenylalanyl-tRNA synthetase. OTB was neither a significant inhibitor of the reaction nor an antagonist of OTA. OTB was also assayed for its possible antagonistic effect on the in vivo protein synthesis inhibition caused by OTA in hepatoma tissue culture cells. No prevention of OTA inhibition could be found for OTB. It rather showed a slight additional inhibitory activity when mixed (100-180 microM) with low concentrations of OTA (40-60 microM). In conclusion, these results are not in favor of an antagonistic effect of OTB with respect to OTA action, at least on the level of cellular protein synthesis.

Animals↗
PubMed2004

Structurally related mycotoxins ochratoxin A, ochratoxin B, and citrinin differ in their genotoxic activities and in their mode of action in human-derived liver (HepG2) cells: implications for risk assessment.

To elucidate the effects of three structurally related mycotoxins, namely, ochratoxin A (OTA), ochratoxin B (OTB), and citrinin (CIT), on human health, we investigated their acute toxic, mitogenic, and genotoxic effects in the human-derived liver cell line (HepG2). These compounds are found in moldy foods in endemic areas of nephropathy, which is associated with urinary tract cancers. In agreement with previous experiments, we found that OTA causes a dose-dependent induction of micronuclei (MN) and DNA migration in the single-cell gel electrophoresis (SCGE) assay, which was statistically significant at concentrations of > or =5 microg/ml. In contrast, OTB was devoid of genotoxic activity under identical conditions, but the compound caused pronounced inhibition of cell division even at doses lower than OTA (10 microg/ml). CIT caused an effect similar to that of OTA in MN assays (significant at dose levels of > or =2.5 microg/ml) but was negative in the SCGE test. All compounds failed to induce mutations in Salmonella/microsome assays in strains TA 98 and TA 100 after addition of HepG2-derived enzyme homogenate (S9-mix). By use of DNA-centromeric probes we found that induction of MN by OTA involves chromosome breaking effects (55-60% of the MN were centromere negative), whereas CIT-induced MN were predominantly centromere positive (78-82%). Our findings indicate that OTB is devoid of genotoxic activity in human-derived cells and therefore probably not a genotoxic carcinogen in humans. In contrast, CIT was an equally potent inducer of MN in HepG2 cells as OTA, but this effect is caused by a different mechanism, namely, aneuploidy. Furthermore, our data suggest that combined exposure to structurally related mycotoxins that cause DNA damage via completely different mechanisms may significantly increase the cancer risk of humans consuming moldy foods.

Cell Line, Tumor↗