Formation of (4R)- and (4S)-4-hydroxyochratoxin A from ochratoxin A by liver microsomes from various species

Størmer, Fredrik C.; Hansen, Ch.; Pedersen, J I; Hvistendahl, Georg; Aasen, Arne Jørgen

doi:10.1128/aem.42.6.1051-1056.1981

Cited by 66 publications

(38 citation statements)

References 7 publications

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“…2 and include: hydroxylated derivatives 4(R)-, 4(S)-and 10-OH-OTA (numbering in Scheme 1 for OTA) and OTalpha (OTa), which lacks the phenylalanine moiety. The 4(R)-OH-OTA metabolite was mainly formed following incubation in presence of human and rat liver microsomes, whereas 4(S)-OH-OTA was essentially formed via pig microsomes [293,296,297] and in the urine of rat [269,298]. The 10-OH-OTA metabolite was detected after in vitro incubation of OTA with rabbit liver microsomes [294].…”

Section: Metabolism Of Otamentioning

confidence: 97%

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Ochratoxin A: An overview on toxicity and carcinogenicity in animals and humans

Pfohl‐Leszkowicz¹,

Manderville²

2006

Molecular Nutrition Food Res

896

525

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Ochratoxin A (OTA) is a ubiquitous mycotoxin produced by fungi of improperly stored food products. OTA is nephrotoxic and is suspected of being the main etiological agent responsible for human Balkan endemic nephropathy (BEN) and associated urinary tract tumours. Striking similarities between OTA-induced porcine nephropathy in pigs and BEN in humans are observed. International Agency for Research on Cancer (IARC) has classified OTA as a possible human carcinogen (group 2B). Currently, the mode of carcinogenic action by OTA is unknown. OTA is genotoxic following oxidative metabolism. This activity is thought to play a central role in OTA-mediated carcinogenesis and may be divided into direct (covalent DNA adduction) and indirect (oxidative DNA damage) mechanisms of action. Evidence for a direct mode of genotoxicity has been derived from the sensitive 32P-postlabelling assay. OTA facilitates guanine-specific DNA adducts in vitro and in rat and pig kidney orally dosed, one adduct comigrates with a synthetic carbon (C)-bonded C8-dG OTA adduct standard. In this paper, our current understanding of OTA toxicity and carcinogenicity are reviewed. The available evidence suggests that OTA is a genotoxic carcinogen by induction of oxidative DNA lesions coupled with direct DNA adducts via quinone formation. This mechanism of action should be used to establish acceptable intake levels of OTA from human food sources.

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Section: Metabolism Of Otamentioning

confidence: 97%

“…The metabolism of OTA has been extensively studied by the team of Størmer during the past 25 years [291] using in vitro and in vivo assays in liver of different animals [292][293][294][295]. The major metabolites are shown in Fig.…”

Section: Metabolism Of Otamentioning

confidence: 99%

Ochratoxin A: An overview on toxicity and carcinogenicity in animals and humans

Pfohl‐Leszkowicz¹,

Manderville²

2006

Molecular Nutrition Food Res

896

525

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“…Metabolism of ochratoxin A (Stormer et al, 1981;Syversten and Stormer, 1983), verruculogen (Perera et al, 1982) and T-2 toxin (Yoshizawa et al, 1982) have also been recently examined. Results suggest these mycotoxins are metabolized by the MFO, but further studies will be necessary to determine if bioactiration is requisite for intoxication.…”

Section: Other Mycotoxinsmentioning

confidence: 99%

Hepatic Metabolism and Bioactivation of Mycotoxins and Plant Toxins

Swick

1984

Journal of Animal Science

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The intoxication of livestock from ingested feed contaminated with naturally occurring toxicants is of great economic importance. Certain toxicants require enzymatic bioactivation before harmful effects are exhibited. In the liver, the cytochrome P-450 dependent mixed function oxidase (MFO) system normally metabolizes foreign compounds (xenobiotics) into more polar, more excretable and less toxic metabolites. During metabolism of aflatoxins and pyrrolizidine alkaloids (PA), oxidized metabolites are highly reactive with cellular components and are more toxic than the parent compounds. Hepatic bioactivation is of considerable importance because active metabolites are formed directly within the tissues of the animal. In addition, the MFO system has only limited specificity and is dependent on many factors including diet, age, sex, species and environmental influences. The interrelationship of these factors on aflatoxicosis and pyrrolizidine alkaloidosis are often responsible for the chronic nature and difficult etiology of these diseases. A better understanding of the factors affecting metabolism and bioactivation of these toxicants may lead to the development of techniques for protecting animals that are subjected to contaminated feeds.

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“…When ochratoxin A is incubated with pig liver microsomes and NADPH, two hydroxylated metabolites, (4R)and (4S)-4-hydroxyochratoxin A, are formed in about equal amounts (8). These metabolites are also formed, but in a different ratio, when microsomes from human or rat livers are used (8).…”

mentioning

confidence: 99%

“…The compounds were dissolved in methanol, and their concentrations were based on the molecular extinction coefficients (molar-1 centimeter-1): ochratoxin A, 5,500 at 333 nm (6); and (4R)-and (4S)-4-hydroxyochratoxin A and 10-hydroxyochratoxin A, 6,400 at 334 nm (2, 8, 9). The metabolites were pure as judged by thin-layer chromatography and high-pressure liquid chromatography (8,9). Samples for kinetic experiments were evaporated under N2 at 40 to 50°C.…”

mentioning

confidence: 99%