Acute Toxicity of Aflatoxin B1 in Rats

Butler, W. H.

doi:10.1038/bjc.1964.87

Cited by 166 publications

(33 citation statements)

References 4 publications

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“…Components of these peaks were separated by using isocratic conditions with a Waters 1ABondapak C18 column eluted with methanol/water, 35:65 (vol/vol), at 500 and 1.0 ml/min. Under these conditions, a major peak was seen at 10 min and several minor ones at 8,6, and 3 min. The major peak (I) was collected in a volume of (16), can be accounted for by rearrangement-the guanine methyl group originating from the methoxyl group of aflatoxin.…”

Section: Methodsmentioning

confidence: 94%

“…This represents approximately 100% of the activity originally present in the nucleic acids. Compounds eluting in fractions [3][4][5][6][7][8][9][10][11] during the wash phase represent 23.7% of the total 3H activity. The radioactive compounds contained in these fractions have not been identi- fied but it is suspected that these peaks contain polar AFB1 deoxyribo-and ribonucleotide derivatives.…”

Section: Methodsmentioning

confidence: 99%

“…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).…”

mentioning

confidence: 99%

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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.

209

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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: 94%

Section: Methodsmentioning

confidence: 99%

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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.

209

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“…: Figure 1. Expression of y-glutamyltranspeptidase (GGT), glutathione S-transferase-p(GST-P), CYP2B1/2, and 3A1 in persistent GGT nodules and remodeling nodules induced by the SoltFarber resistance protocol in semi-serial sections (17 (22)(23)(24). We also observed extensive periportal necrosis in the livers of rats given the AFB protocol.…”

Section: Responsiveness To Phenobarbital Induction and Zonal Origin Imentioning

confidence: 76%

Association between Responsiveness to Phenobarbital Induction of CYP2B1/2 and 3A1 in Rat Hepatic Hyperplastic Nodules and Their Zonal Origin

Chen¹,

Eaton²

1993

Environmental Health Perspectives

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To explore further the mechanism underlying the alteration in expression of P450 enzymes in hepatic preneoplastic lesions, expression of CYP2B1/2 and 3A1 in individual hepatic hyperplastic nodules induced by an aflatoxin B, (AFB) administration protocol and the Solt-Farber resistance protocol in male F344 rats was examined via immunohistology. In nodules induced by the resistance protocol, expression of both CYP2B1/2 and 3A1 proteins was highly variable among different nodules, whereas these P450 proteins were expressed in all nodules induced by the AFB protocol. Nodules induced by the resistance protocol have been shown previously to arise from throughout the acinar lobule. In contrast to the resistance protocol, the AFB protocol causes extensive periportal necrosis, potentially resulting in a heavy selection pressure for clonal expansion of initiated cells arising from the centrilobular area. As phenobarbitalinduced expression of both CYP2B1/2 and 3A1 in normal liver is heavily localized to the centrilobular zone, these observations suggest that the ability of preneoplastic nodules to respond to induction of these P450 proteins is deternined primarily from the zonal origin of the precursor hepatocytes. Thus, the nodules from the resistance protocol that express little or no CYP2B1/2 and 3A1 may have been derived from the periportal hepatocytes, whereas all the nodules in the AFB group and some of the nodules from the resistance protocol which expressed these P450 proteins in response to phenobarbital induction may have been derived from centrilobular hepatocytes.

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“…Masri et al (196"7) have shown that 0.3% of an administered dose of aflatoxin B' appeared in milk (aflatoxin M,) within a few hours. M. is the 4-hydroxy-aflatoxin derivative of B, (Goldblat 1969 (Butler 1964). Therefore, feed contamination could result in prolonged impairment of livestock performance (Lynch 1972).…”

mentioning

confidence: 99%

Organic Acid Preservation of High Moisture Corn and Other Grains and the Nutritional Value: A Review

Jones¹,

Elliot²,

Mowat³

et al. 1974

Can. J. Anim. Sci.

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In, 1974, Or-ganic acid preservation of high moisture corn and other grains and the nutritional value: A review. Can. J. Anim. Sci. 54 499-517. The subject is reviewed with respect to the preservation of high moisture grains with organic acids and the subsequent performance of dairy and beef cattle, swine and poultry fed rations containing this feedstuff. The importance of preventing mold growth and thereby aflatoxin production is discussed briefly. Various types of grain preservatives and application rates ale examined. The economic implications of the use of grain preservatives are explored. Grain preserved in this manner has been readily accepted by livestock and has supported high levels of milk production or rapid weight gains. It is a practical method of storing high moisture grain and is competitive with artificial drying or ensiling in silos.Les auteurs font une mise b jour de la question de la conservation des c6r6ales humides par les acides organiques, et de

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Acute Toxicity of Aflatoxin B1 in Rats

Cited by 166 publications

References 4 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.

Association between Responsiveness to Phenobarbital Induction of CYP2B1/2 and 3A1 in Rat Hepatic Hyperplastic Nodules and Their Zonal Origin

Organic Acid Preservation of High Moisture Corn and Other Grains and the Nutritional Value: A Review

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