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.
| Medienart: |
Artikel |
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| Erscheinungsjahr: |
2001 |
|---|---|
| Erschienen: |
2001 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:59 |
|---|---|
| Enthalten in: |
Toxicological sciences : an official journal of the Society of Toxicology - 59(2001), 1 vom: 02. Jan., Seite 59-67 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Zepnik, H [VerfasserIn] |
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| Anmerkungen: |
Date Completed 22.02.2001 Date Revised 13.05.2019 published: Print Citation Status MEDLINE |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM110487451 |
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| 245 | 1 | 0 | |a Ochratoxin A-induced tumor formation |b is there a role of reactive ochratoxin A metabolites? |
| 264 | 1 | |c 2001 | |
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| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
| 650 | 7 | |a Carcinogens |2 NLM | |
| 650 | 7 | |a Isoenzymes |2 NLM | |
| 650 | 7 | |a Mycotoxins |2 NLM | |
| 650 | 7 | |a Ochratoxins |2 NLM | |
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| 700 | 1 | |a Schauer, U |e verfasserin |4 aut | |
| 700 | 1 | |a Dekant, W |e verfasserin |4 aut | |
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