<b>Aflatoxins B and G</b>

Asao, Toyonobu.; Büchi, G.; Abdel-Kader, M. M.; Chang, S. B.; Wick, Emily L.; Wogan, G. N.

doi:10.1021/ja00894a050

Cited by 275 publications

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“…Rats (130-150 g) were injected intraperitoneally with AFB1 at 2 mg/kg, purified by the method of Asao et al (19) in 50 Ml of dimethyl sulfoxide (Burdick and Jackson Laboratories, Muskegon, MI). Rats were stunned and decapitated 2 hr after dosing.…”

Section: Methodsmentioning

confidence: 99%

Identification of the principal aflatoxin B1-DNA adduct formed in vivo in rat liver.

Croy¹,

Essigmann²,

Reinhold³

et al. 1978

Proc. Natl. Acad. Sci. U.S.A.

207

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The products of in vivo covalent binding of activated aflatoxin B1 (AFB1) to DNA have been investigated in rats. The principal covalent product formed in liver DNA of rats treated with AFB1 has been identified as 2,3-dihydro-2-(N7-guanyl)3hydroxy-aflatoxin B1. This compound was isolated from the liver DNA of rats dosed with AFB1 (2.0 mg/kg) in sufficient quantity for characterization by physicochemical techniques, including field-desorption mass spectrometry. This information together with results of chemical methylation of the compound proved that the major adduct formed between DNA and AFB1 in vivo is identical to that produced in vitro when AFB1 is incubated with DNA in the presence of a rat liver microsomal activating system. Quantitative studies of formation of this compound revealed a dose-ependent relationship between the level of its occurence in liver DNA and AFB1 doses over the range 0.125-1.0 mg/kg. Aflatoxin B1 (AFB1), a secondary fungal metabolite of several species of the genus Aspergillus, is acutely toxic to most animal species, although sensitivity varies widely. The rat, rainbow trout and duck are among the most susceptible to its toxic effects. AFB1 is also a potent hepatocarcinogen in these species (1) and is a potent mutagen in mammalian and bacterial cells (2-4). Epidemiological investigations in several human populations have revealed an association of increased incidences of hepatocellular carcinoma with increasing dietary contamination by AFB1 (5).Biological effects of AFB1 have been extensively studied in the rat. Acute doses of the toxin in this species produce both morphological and biochemical alterations primarily associated with the liver (6). Reversible inhibition of RNA synthesis has been demonstrated in vivo (7,8) and has been shown to be temporally associated with nucleolar segregation (9). DNA synthesis is also reversibly inhibited in normal (10) and partially hepatectomized (8, 11) animals following acute doses of the toxin.Investigations of various in vitro models have demonstrated the requirement for metabolic conversion of AFB1 to an active derivative which interacts covalently with DNA (12) and results in alterations of normal biochemical processes associated with it such as transcription and replication (8).Covalent binding of AFB1 to DNA in vitro is dependent on microsomal conversion of AFB1 to the reactive 2,3-exo-epoxide. Although this labile molecular species has not been isolated, much indirect evidence has accumulated to substantiate its transient existence (13,14). Covalent binding in vivo to nucleophilic atoms in proteins and nucleic acids is also thought to be mediated through metabolic activation to this reactive compound (15). Identification of the reactive sites in these macromolecules and the covalent compounds formed with AFB1 may provide a more complete understanding of its biological effects and provide further information on which to base hypotheses concerning the mechanisms underlying its carcinogenic properties.The nucleophilic sites of intera...

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Section: Methodsmentioning

confidence: 99%

Identification of the principal aflatoxin B1-DNA adduct formed in vivo in rat liver.

Croy¹,

Essigmann²,

Reinhold³

et al. 1978

Proc. Natl. Acad. Sci. U.S.A.

207

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“…It was early recognized that both substances contain the lactone grouping and associated ac,#-unsaturated bonds. Finally (Asao et al, 1963) In previous papers (Dickens andJones, 1961, 1963;Dickens, 1962Dickens, , 1964 we have studied the effects on the rat of administration of a group of unsaturated lactones and have found that a number of y-and &-lactones in the chemical structure of which the carbonyl function is conjugated with one or more double bonds, are carcinogenic. In all cases tested, prolonged administration proved necessary for carcinogenesis, but with this provision a high proportion of rats developed local tumours at the subcutaneous injection site with reasonably small doses (0.1-2 mg.) of the more highly carcinogenic lactones in this series.…”

mentioning

confidence: 98%

“…Two major and two or more minor toxic components were present-they were named Aflatoxins, after the mould, and distinguished on the basis of their blue or green fluorescence as aflatoxins B or G respectively, the main components of the crystalline toxin being named B1 and G1 (van der Zijden et al, 1962;Nesbitt et al, 1962;Asao et al, 1963). Aflatoxin B1, C17H1206, has the highest toxicity (LD50 for 51 g. day-old ducklings, 28 jag.…”

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confidence: 99%

The Carcinogenic Action of Aflatoxin after its Subcutaneous Injection in the Rat

Dickens¹,

Jones²

1963

Br J Cancer

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“…Later, feeding similar purified toxin to rats was shown to lead to hepatoma formation, like the contaminated meal (Barnes and Butler, 1964). Chemical studies at the Massachusetts Institute of Technology have now revealed that both purified aflatoxins B1 and G1 contain respectively one or two 6-membered lactone rings possessing oc,-unsaturation which is conjugated directly with further double bonds in the molecule (Asao et al, 1963; see also Dickens and Jones, 1963b). Whether the remaining parts of these fairly complex molecules are involved in their carcinogenicity remains to be studied.…”

Section: Further Studies On the Carcinogenic Action Of Certain Lactonmentioning

confidence: 99%

Further Studies on the Carcinogenic Action of Certain Lactones and Related Substances in the Rat and Mouse

Dickens¹,

Jones²

1965

Br J Cancer

134

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On the other hand, in the lactones hitherto tested, absence of xfl-unsaturation, as in the fly-unsaturated a-angelica lactone and in the fully saturated y-butyro lactone, or opening of the lactone ring by hydrolysis, resulted in loss of carcinogenicity.In the case of the remarkably highly carcinogenic unsaturated lactone represented by the mould-product aflatoxin, the chemical structure of this compound was not known at the time when groundnut meal infected with Aspergillus fiavus was first shown to constitute a hepato-carcinogenic diet for the rat (Lancaster, Jenkins and Philp, 1961 ; see also Butler and Barnes, 1963). The purified toxin (mixed aflatoxins B1 and G1), made available to us by the Tropical Products Institute, D.S.I.R., London, was shown to produce local malignant tumours at the injection site in rats in doses as low as 50 ,tg (Dickens and Jones, 1963b). Later, feeding similar purified toxin to rats was shown to lead to hepatoma formation, like the contaminated meal (Barnes and Butler, 1964). Chemical studies at the Massachusetts Institute of Technology have now revealed that both purified aflatoxins B1 and G1 contain respectively one or two 6-membered lactone rings possessing oc,-unsaturation which is conjugated directly with further double bonds in the molecule (Asao et al., 1963; see also Dickens and Jones, 1963b). Whether the remaining parts of these fairly complex molecules are involved in their carcinogenicity remains to be studied.In the present paper we have extended the above observations in various directions. In the first place, we have added further tests on coumarin (I) (since the coumarin ring is contained in the aflatoxins), and on coumalic acid (II) a near relative: unfortunately both compounds proved highly toxic. The same applied to N-ethyl maleimide (III), a nitrogen analogue of maleic anhydride and a powerful sulphydryl-reacting material.

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Aflatoxins B and G

Cited by 275 publications

References 0 publications

Identification of the principal aflatoxin B1-DNA adduct formed in vivo in rat liver.

Identification of the principal aflatoxin B1-DNA adduct formed in vivo in rat liver.

The Carcinogenic Action of Aflatoxin after its Subcutaneous Injection in the Rat

Further Studies on the Carcinogenic Action of Certain Lactones and Related Substances in the Rat and Mouse

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