Ochratoxin A

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Ochratoxin A
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Executive Summary Information

Compound Ochratoxin A (OTA)
Toxicities Renal carcinogenicity and nephrotoxicity.
Mechanisms Non-genotoxic carcinogen. It is likely that it interferes with cytoskeletal structures causing aberrant mitosis.
Comments This compound was chosen for the study of epigenetic effects in renal cells. SAFETY CAUTION: This compound is one of the most potent renal carcinogens known in rats and should be handled with extreme care.
Feedback Contact Gold Compound Working Group (GCWG)
Ochratoxin A
Ochratoxin A.png


Identifiers
Leadscope Id LS-1157
CAS 303-47-9
ChemSpider 390954
ChEBI 7719
Pathway DBs
KEGG C09955
Assay DBs
PubChem CID 442530
ChEMBL 589366
Omics DBs
Properties
ToxCast Accepted no
ToxBank Accepted yes
Approved on 2012-10-23


In Vivo Data ? Compound Assessment
Adverse Events ? Ochratoxins are a family of structurally related mycotoxins which are produced as secondary metabolites in Aspergillus and Penicillium s pecies. They are found in a wide variety of foods including cereals, meat, dried fruits, nuts, coffee, wine and beer. Ochratoxin A (OTA) is the most toxic of the family and its main target is the renal proximal tubular epithelium, likely due to basolateral uptake via the organic anion transporter.

References:

-Zlender, V., Breljak, D., Ljubojevic, M., Flajs, D., Balen, D., Brzica, H., Domijan, A.M., Peraica, M., Fuchs, R., Anzai, N., et al. (2009). Low doses of ochratoxin A upregulate the protein expression of organic anion transporters Oat1, Oat2, Oat3 and Oat5 in rat kidney cortex. Toxicol Appl Pharmacol 239, 284-296.

OTA is found at highest concentrations in European food with the average daily intake of a European adult of 1 ng kg-1 b.w. but increasing to 6-8 ng kg-1 b.w. for high consumers.

References:

-Clark, H.A., and Snedeker, S.M. (2006). Ochratoxin a: its cancer risk and potential for exposure. J Toxicol Environ Health B Crit Rev 9, 265-296.
-SCOOP (2002). Reports on tasks for scientific cooperation: Assessment of dietary intake of Ochratoxin A by the population of EU member states. Link

OTA is both a nephrotoxin and a renal carcinogen. It has the highest incidence of renal tumours in male rats of any compound tested by the NTP and exhibits high metastatic potential

References:

-Boorman, G.A., McDonald, M.R., Imoto, S., and Persing, R. (1992). Renal lesions induced by ochratoxin A exposure in the F344 rat. Toxicol Pathol 20, 236-245.
-NTP (1989). Toxicology and Carcinogenesis Studies of Ochratoxin A in F344/N Rats (Gavage Studies). Natl Toxicological Program Tech Rep Ser, 1-142.
Toxicity Mechanisms ? The mechanism of OTA carcinogenicity remains elusive and somewhat controversial, the weight of evidence points to a non-genotoxic mechanism, likely via an epigenetic mechanism resulting from oxidative stress and cytotoxicity

References:

-Mally, A., and Dekant, W. (2009). “Mycotoxins and the kidney: modes of action for renal tumor formation by ochratoxin A in rodents”, Mol Nutr Food Res 53, 467-478
-Turesky, R.J. (2005). “Perspective:ochratoxin A is not a genotoxic carcinogen”, Chem Res Toxicol 18, 1082-1090

A recent in vitro study with several human and rat proximal tubule cell lines showed that OTA exposure resulted in large transcriptomic alterations, reflecting perturbations in cytoskeleton regulation, nucleosome regulation, translation, transcription, ubiquitination and cell cycle pathways. The authors suggest an epigenetic model for OTA effects.

References:

-Jennings, P., Weiland, C., Limonciel, A., Bloch, K.M., Radford, R., Aschauer, L., McMorrow, T., Wilmes, A., Pfaller, W., Ahr, H.J., et al. (2012). Transcriptomic alterations induced by Ochratoxin A in rat and human renal proximal tubular in vitro models and comparison to a rat in vivo model. Arch Toxicol 86, 571-589.
Therapeutic Target ? OTA is not used therapeutically.

PK-ADME ? Compound Assessment
PK parameters ? OTA has a long half life due to its high affinity for protein binding. Elimination of OTA from blood follows first-order kinetics with a half-life of approximately 230 h.

References:

-Zepnik, H., Volkel, W., and Dekant, W. (2003). Toxicokinetics of the mycotoxin ochratoxin A in F 344 rats after oral administration. Toxicol Appl Pharmacol 192, 36-44.
Therapeutic window ? Not applicable
Metabolically activated ? It is thought that the parent compound is toxic. OTA is metabolized at a low level, with OTalpha its major metabolite formed by a cleavage of the peptide by peptidases like carboxypeptidase A or by acid hydrolysis. The presence of two further metabolites with ion transitions identical to OTA, e.g., of 402/167, but with different chromatographic properties, have been observed in urine samples.

References:

-Zepnik, H., Volkel, W., and Dekant, W. (2003). Toxicokinetics of the mycotoxin ochratoxin A in F 344 rats after oral administration. Toxicol Appl Pharmacol 192, 36-44.

Omics and IC50 Data ? Compound Assessment
Gene expression profiles known. ?

References:

-Arbillaga, L., Azqueta, A., van Delft, J.H., and Lopez de Cerain, A. (2007). In vitro gene expression data supporting a DNA non-reactive genotoxic mechanism for ochratoxin A. Toxicol Appl Pharmacol 220, 216-224.
-Arbillaga, L., Vettorazzi, A., Gil, A.G., van Delft, J.H., Garcia-Jalon, J.A., and Lopez de Cerain, A. (2008). Gene expression changes induced by ochratoxin A in renal and hepatic tissues of male F344 rat after oral repeated administration. Toxicol Appl Pharmacol 230,197-207
-Jennings, P., Weiland, C., Limonciel, A., Bloch, K.M., Radford, R., Aschauer, L., McMorrow, T., Wilmes, A., Pfaller, W., Ahr, H.J., et al. (2012). Transcriptomic alterations induced by Ochratoxin A in rat and human renal proximal tubular in vitro models and comparison to a rat in vivo model. Arch Toxicol 86, 571-589.
-Luhe, A., Hildebrand, H., Bach, U., Dingermann, T., and Ahr, H.J. (2003). A new approach to studying ochratoxin A (OTA)-induced nephrotoxicity: expression profiling in vivo and in vitro employing cDNA microarrays. Toxicol Sci 73, 315-328.
Proteomics profiles known. ? None Found
Metabonomics profiles known. ?

References:

-Ellis JK, Athersuch TJ, Cavill R, Radford R, Slattery C, Jennings P, McMorrow T, Ryan MP, Ebbels TM, Keun HC. Metabolic response to low-level toxicant exposure in a novel renal tubule epithelial cell system. Mol Biosyst.

2011 Jan;7(1):247-57. Epub 2010 Nov 19. PubMed pmid:21103459

.
Fluxomics profiles known. ?
Epigenomics profiles known. ? No actual profiling found, but epigenetic effects are thought to be a main mechanism of toxicity. Reviewed in

References:

-Marin-Kuan M, Cavin C, Delatour T, Schilter B. Ochratoxin A carcinogenicity involves a complex network of epigenetic mechanisms. Toxicon. 2008 Aug 1;52(2):195-202. Epub 2008 May 29. Review. pmid:18649906

Additionally, transcriptomics data also suggest epigenetic effects as a main mechanism.

References:

-Jennings, P., Weiland, C., Limonciel, A., Bloch, K.M., Radford, R., Aschauer, L., McMorrow, T., Wilmes, A., Pfaller, W., Ahr, H.J., et al. (2012). Transcriptomic alterations induced by Ochratoxin A in rat and human renal proximal tubular in vitro models and comparison to a rat in vivo model. Arch Toxicol 86, 571-589.
Observed IC50 for in vitro cellular efficacy. ? Not Applicable
Observed IC50 for in vitro cellular toxicity studies. ? 0.3 to 5 µM reported as stress activating but non-cytotoxic.

References:

-Jennings, P., Weiland, C., Limonciel, A., Bloch, K.M., Radford, R., Aschauer, L., McMorrow, T., Wilmes, A., Pfaller, W., Ahr, H.J., et al. (2012). “Transcriptomic alterations induced by Ochratoxin A in rat and human renal proximal tubular in vitro models and comparison to a rat in vivo model”, Arch Toxicol 86, 571-589.

50 µM in RPTEC/TERT1 cells at 96 h

References:

-carcinoGENOMICs internal report, Jennings.

Physical Properties ? Compound Assessment
Accepted and listed within the ToxCast/Tox21 program. ? Yes - Included in ToxCast Phase I and II Chemicals List
Substance stability. ?
Soluble in buffer solution at 30 times the in vitro IC50 for toxicity. ? Water solubility 14 mg/ml (~100 mM) (25°C)

References:

-YALKOWSKY,SH & HE,Y (2003) from SRC PhysProp Database

Water solubility 16.7 mg/ml (~100 mM) (25°C)

References:

-Mota FL, Carneiro AP, Queimada AJ, Pinho SP, Macedo EA. Temperature and solvent effects in the solubility of some pharmaceutical compounds: measurements and modeling. Eur J Pharm Sci 2009; 37: 499-507.


estimated intrinsic solubility : 17.8 mg/ml
estimated solubility in pure water at pH 5.70: 17.8 mg/ml
estimated solubility in water at pH 7.4: 17.9 mg/ml
Calculations performed using ACD/PhysChem v 9.14

Solubility in DMSO 100 times buffer solubility. ? 5 M Sigma Aldrich A7085 Product details
Vessel binding properties. ?
Vapor pressure. (Non-volatile) ? estimated vapor pressure: 1.94E-06 mmHg (Calculation performed using EPI Suite v4.10)


Calculated/Predicted Properties

Water Solubility Results
pH Sol, mg/ml 9+ 0 10- Graph
2 21.96 18.8 81.2 - Acetaminophen solubility.png
5.5 17.85 - 100 -
6.5 17.85 - 100 -
7.4 17.9 - 99.7 0.3
10 40.62 - 43.9 56.1
Summary Solubility Data
Intrinsic Solubility, mg/ml 17.8454
Intrinsic Solubility, log(S, mol/l) -0.9279
Solubility in Pure Water @pH = 5.7, mg/ml 17.8474
Calculations performed using ACD/PhysChem v 9.14
LogD Results
pH LogD Graph
2 0.25 Acetaminophen logd.png
5.5 0.34
6.5 0.34
7.4 0.34
10 -1.86E-2
Calculations performed using ACD/PhysChem v 9.14
Single-valued Properties
Property Value Units Error
LogP 0.34 0.21
MW 151.16 -
PSA 49.33 -
FRB 2 -
HDonors 2 -
HAcceptors 3 -
Rule Of 5 0 -
Molar Refractivity 42.41 cm3 0.3
Molar Volume 120.95 cm3 3
Parachor 326.03 cm3 4
Index of Refraction 1.62 0.02
Surface Tension 52.8 dyne/cm 3
Density 1.25 g/cm3 0.06
Polarizability 16.81 10E-24 cm3 0.5
Calculations performed using ACD/PhysChem v 9.14
Property Name Value Units Source
pKa 9.48 SPARC v4.5
Estimated VP 1.94E-06 mm Hg EPI Suite v4.10
Estimated VP 2.586E-04 Pa EPI Suite v4.10
Estimated Water Solubility 3.04E+04 mg/L EPI Suite v4.10
WATERNT Frag Water Solubility Estimate 2.37E+05 mg/L EPI Suite v4.10
pKa Results
Acidic/Basic Acidic/Basic Apparent pKa Value Error Source
9 A 15.32 0.7
10 MA 9.86 0.13
9 MB 1.72 0.5
A = Acidic
B = Basic
MA = Most Acidic
MB = Most Basic
Calculations performed using ACD/PhysChem v 9.14


Authors of this ToxBank wiki page

David Bower
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