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PubMed1978

[Occurrence of aflatoxins in pig feed].

Sixty-seven pig feed samples were examined for the presence of aflatoxins by the method after Velasco, with simultaneous qualitative determination by the thin-layer chromatographic method. All samples were collected at about the same time (June 1977) from central stores, feed preparing plants, storage containers and feeding lines on farms. On the whole, the feeds formed a representative sample of the conditions of pig feed storage and treatment. The presence of aflatoxins was proved in 18 samples (26.8%). One sample (1.4%) showed just traces of aflatoxin, six samples (8.4%) contained 0.014 to 0.45 mg aflatoxins, eight samples (11.2%) contained 0.10 to 0.30 mg aflatoxins, and three samples (4.2%) had 2.7 to 3.5 mg aflatoxins per 1 kg of feed. The samples with the highest aflatoxin concentrations came from metallic storage containers for complete feed mixtures in front of the pigsties.

Aflatoxins↗

PubMed1986

Aflatoxins and kwashiorkor: clinical studies in Sudanese children.

Aflatoxin analysis of blood and urine by high performance liquid chromatography in 584 Sudanese children is reported. The results in 404 malnourished children comprising 141 kwashiorkor, 111 marasmic kwashiorkor and 152 with marasmus are compared with 180 age-matched controls and correlated with clinical findings. The aflatoxin detection rate and mean concentration were higher in serum of children with kwashiorkor than the other groups. The difference between the detection rate in kwashiorkor and controls was significant (p less than 0.05). The aflatoxin detection rate in urine was highest in the marasmic kwashiorkor group and the mean concentration was higher in the marasmic kwashiorkor and marasmic groups than in the kwashiorkor and control groups. There were important differences in the detection of certain aflatoxins between the groups. Aflatoxicol was detected in the sera of 16 (11.6%) kwashiorkor, in six (6.1%) marasmic kwashiorkor, but in none of the controls and only once in marasmus. These differences are highly significant (p less than 0.0001). The ratio of AFB1 to AFM1 was higher in the sera and urines of kwashiorkors than in controls, suggesting that the normal transformation of AFB1 to AFM1 may be impaired in kwashiorkor with consequent increase in transformation of AFB1 to aflatoxicol. The study therefore provides evidence of differences in the metabolism of aflatoxins in children with kwashiorkor compared with children with other forms of malnutrition and normally nourished children and confirms the association between aflatoxins and kwashiorkor contained in a preliminary report on this work.

Aflatoxin B1↗

PubMedDate not supplied

Fractionation of radioactivity in the milk of goats administered 14C-aflatoxin B1.

A detailed fractionation of radioactivity in the milk of goats administered 14C-aflatoxin B1 at low doses was performed. The milk collected in the first 24 h following dosing contained radioactivity equivalent to 0.45-1.1% of the dose given. The radioactivity in each sample was partitioned into 4 fractions: ether, protein, dichloromethane, and water-alcohol. Over 80% of the radioactivity was detected in the dichloromethane fraction, of which over 95% was attributable to aflatoxin M1. No aflatoxin B1 or other known aflatoxin metabolites were detected in any fraction. The results indicate that the major metabolite of aflatoxin B1 in goat milk is aflatoxin M1 and that other metabolites, including conjugates, are of minor significance.

Aflatoxin B1↗

PubMed1998

Genetics and physiology of aflatoxin biosynthesis.

Aflatoxins are the most thoroughly studied mycotoxins. Elegant early research on the biosynthetic scheme of the pathway has allowed a molecular characterization of aflatoxin biosynthesis and its regulation. Genetic studies on aflatoxin biosynthesis in Aspergillus flavus and A. parasiticus, and sterigmatocystin biosynthesis in A. nidulans, led to the cloning of 17 genes responsible for 12 enzymatic conversions in the AF/ST pathways. Pathway-specific regulation is by a Zn(II)2Cys6 DNA-binding protein that regulates the transcription of all pathway genes. Less is known about the global factors that regulate aflatoxin biosynthesis, but there is a clear link between development and aflatoxin biosynthesis. There is also a large body of information on physiological factors involved in aflatoxin biosynthesis, but it has been difficult to understand their role in the regulation of this pathway. This chapter discusses current knowledge on the molecular biology and genetics of the pathway, and provides a summary of the physiological factors known to influence aflatoxin formation.

Journal Article↗

PubMed1993

Resistance to aflatoxin B1 is associated with the expression of a novel aldo-keto reductase which has catalytic activity towards a cytotoxic aldehyde-containing metabolite of the toxin.

Fischer 344 rats readily develop liver cancer when exposed to aflatoxin B1 (AFB1) but dietary administration of the antioxidant ethoxyquin (EQ) provides protection against hepatocarcinogenesis. Chemoprotection by EQ is accompanied by the overexpression of enzymes which detoxify activated AFB1. Aflatoxin-protein adduct formation takes place following metabolism of AFB1 to the dialdehydic form of AFB1-dihydrodiol. The dialdehyde can be detoxified by reduction to a dialcohol through the catalytic actions of an enzyme present in the hepatic cytosol from rats fed EQ-containing diets; this metabolite is essentially undetectable in reaction mixtures that use hepatic cytosol from rats fed control diets. The enzyme responsible for catalyzing the formation of dihydroxy-aflatoxin B1 has been purified from the livers of rats fed on diets supplemented with EQ. It is a soluble monomeric protein with an approximate M(r) of 36,600. Besides its activity toward AFB1 this enzyme also catalyzes the reduction of the model substrate 4-nitrobenzaldehyde. Amino acid sequencing of cyanogen bromide-derived peptides obtained from this reductase indicated that it has not been characterized hitherto, at least not a molecular level. Therefore, this inducible enzyme has been designated aflatoxin B1-aldehyde reductase (AFB1-AR). The livers of adult rats administered dietary EQ contain at least 15-fold greater levels of AFB1-AR than the livers from rats fed control diets. Aflatoxin B1-AR was also found to be present in increased amounts in livers bearing preneoplastic nodules and in rat hepatoma, both of which are known to express increased resistance to AFB1. Kidney contains high constitutive levels of AFB1-AR and the administration of EQ increases its concentration in renal cytosol about 3-fold. Although AFB1-AR is present in trace amounts in rat lung it was not detected in brain and in neither tissue was it found to be induced by EQ. Evidence suggests that AFB1-AR is a previously unrecognized enzyme that could provide protection against the cytotoxic effects of aflatoxin B1 resulting from the formation of protein adducts. The relative importance of AFB1-AR and the glutathione-S-transferase Yc2 subunit in conferring resistance to aflatoxin B1 is discussed.

Aldehyde Reductase↗

PubMed1990

Genetic analysis of aflatoxin B1 activation in rat hepatoma cells.

We present a strategy to elucidate the rate-limiting steps in activation of carcinogenic compounds by cytochromes P450. The principle was to select Reuber rat hepatoma cells for resistance to a procarcinogen. The hypothesis was that resistant cells should be systematically deficient in the P450 enzyme(s) involved in the activation process. Here we present an example of the use of this approach using aflatoxin B1 (AFB1), a potent hepatocarcinogen, as the selective agent. Parental cells as well as individual and pooled colonies selected for AFB1 resistance from three independent rat hepatoma lines were characterized for their content of 1) mRNA hybridizing to cDNA and/or oligonucleotide probes for cytochromes P450IIB1, P450IIB2 and albumin; and 2) aldrin epoxidase activity. Parental aflatoxin B1-sensitive cells were shown to express P450IIB1 but not P450IIB2. The majority of the aflatoxin B1-resistant clones failed to accumulate cytochrome P450IIB1 mRNA and expressed no or only very low aldrin epoxidase activity. Albumin mRNA levels remained unchanged, demonstrating that loss of expression of cytochrome P450IIB1 was not a consequence of a general dedifferentiation event. A revertant population showing restoration of both cytochrome P450IIB1 mRNA accumulation and aldrin epoxidase activity was fully sensitive to aflatoxin B1. The correlation between expression of cytochrome P450IIB1 and sensitivity to aflatoxin B1 in both parental cells and revertants strongly suggests that cytochrome P450IIB1 is a major contributor to the activation of aflatoxin B1 in rat hepatoma cells. The kind of strategy described here could be applied to other compounds that become cytotoxic for hepatoma cells following activation by cytochromes P450.

Aflatoxin B1↗

PubMed1982

The potential value of silage in detoxifying aflatoxin B1.

Serial concentrations of aflatoxin B1 ranging from 200 to 1500 p.p.b. in 2% lactic acid solution (which is the aimed concentration of lactic acid in fresh silage) were assayed for detoxification. Thin-layer chromatography analysis, revealed a complete transformation of 1 000 p.p.b. of aflatoxin B1 to a new fluorescing compount corresponding to aflatoxin B2a which is referred to as hydroxydihydro-aflatoxin B1 toxicity test on chickens confirmed Ciegler's findings (4). The results confirm that the chemical changes taken place in the silo can detoxify aflatoxin B1 to aflatoxin B2a.

Aflatoxin B1↗

PubMed1985

Fluorescence energy transfer measurements of the complexes of aflatoxin B1 and cytochromes P-450.

The distances between the heme of cytochrome P-450 and the substrate, aflatoxin B1, in the complex of aflatoxin B1 and each of two species of cytochrome P-450 were determined by fluorescence energy transfer measurements. Cytochromes P-450 used were cytochrome P-450 I-d and cytochrome P-450 II-a prepared from hepatic microsomes of polychlorinated biphenyl-treated rats; the main metabolic products of aflatoxin B1 were aflatoxin Q1 and aflatoxin M1, respectively. The distances between the heme and the substrate were calculated to be 6.9nm and 4.7nm in cytochrome P-450 I-d and cytochrome P-450 II-a, respectively. The results suggest that the difference in the metabolic products of aflatoxin B1 is due to the difference in the conformation of the enzyme-substrate complexes.

Aflatoxin B1↗

PubMed1986

The in vitro metabolism of aflatoxin B1 catalyzed by hepatic microsomes isolated from control or 3-methylcholanthrene-stimulated rats and quail.

The rate of microsomal metabolism of aflatoxin B1 (AFB1) by the male quail hepatic microsomal polysubstrate monooxygenase P-450 in vitro was eight times greater than that catalyzed by male rat cytochrome. In the quail almost all the metabolism proceeded via 8,9-aflatoxin B1 epoxidation (assessed by Tris-AFB1-8,9-dihydrodiol formation), whereas in the rat only 36% of soluble metabolites were by this pathway. Pretreatment with 3-methylcholanthrene in the quail resulted in a 9-fold induction of cytochrome P-450 per unit liver weight, but only a 1.7-fold increase in the rate of aflatoxin B1 metabolism. In the rat the corresponding inductions were 1.7 and 1.3, respectively. The aflatoxin B1 metabolism catalyzed by control and 3-methylcholanthrene-stimulated quail microsomes differed qualitatively from that observed with the corresponding fractions from the rat. It was concluded that not only do the basal aflatoxin B1 microsomal metabolism of rat and quail differ, but also that 3-methylcholanthrene induces cytochromes with very different properties in the two species. Assays of ethoxyresorufin O-deethylase activities and polyacrylamide gel electrophoresis analyses further demonstrated these differences between the species. These studies provide further insight into the metabolic differences underlying individual species sensitivities to aflatoxin B1.

Absorption↗

PubMed1995

Cellular interactions and metabolism of aflatoxin: an update.

The aflatoxins are a group of closely related mycotoxins that are widely distributed in nature. The most important of the group is aflatoxin B1 (AFB1), which has a range of biological activities, including acute toxicity, teratogenicity, mutagenicity and carcinogenicity. In order for AFB1 to exert its effects, it must be converted to its reactive epoxide by the action of the mixed function mono-oxygenase enzyme systems (cytochrome P450-dependent) in the tissues (in particular, the liver) of the affected animal. This epoxide is highly reactive and can form derivatives with several cellular macromolecules, including DNA, RNA and protein. Cytochrome P450 enzymes may additionally catalyse the hydroxylation (to AFQ1 and AFM1) and demethylation (to AFP1) of the parent AFB1 molecule, resulting in products less toxic than AFB1. Conjugation of AFB1 to glutathione (mediated by glutathione S-transferase) and its subsequent excretion is regarded as an important detoxification pathway in animals. Resistance to AFB1 toxicity has been interpreted in terms of levels and activities of these detoxifying pathways. This article reviews the multiple reactions and effects attributed to aflatoxin, with particular reference to the interaction of aflatoxin with nucleic acids and proteins, and the contribution this mycotoxin has in disease development and in the promotion of hepatocellular carcinoma (HCC). The anti-mutagenic properties of several dietary factors are also considered in this article. Undoubtedly, the most important aspect of aflatoxin action is its putative role in the development of human cancer, in particular, HCC. Recently, there has been a renewed interest in this aspect and experimental evidence is rapidly accumulating at the molecular level, indicating aflatoxin as an important consideration in the aetiology of human HCC.

Abnormalities, Drug-Induced↗

PubMed1984

The effects of butylated hydroxytoluene on the in vitro metabolism, DNA-binding and mutagenicity of aflatoxin B1 in the rat.

Butylated hydroxytoluene pretreatment in the rat enhanced the total in vitro metabolism of aflatoxin B1 by the hepatic postmitochondrial fraction (S-9) and increased the formation of aflatoxin M1, aflatoxin Q1 and a metabolite tentatively identified as the aflatoxin-glutathione conjugate, the latter being the major metabolite produced. Addition of diethyl maleate, a glutathione depletor, to the incubation mix, reduced formation of the conjugate. No significant difference between treated and control animals was observed in the S-9-mediated binding of aflatoxin B1 to calf thymus DNA. However, the mutagenicity of aflatoxin B1 in Salmonella typhimurium TA98 was significantly lower in the presence of S-9 from BHT-treated rats than with S-9 from controls.

Aflatoxin B1↗

PubMed1984

Effects of saturated and unsaturated dietary fat on aflatoxin B1 metabolism.

Male Fisher 344 rats were fed diets containing either 20% corn oil, 20% coconut oil or 18% coconut oil plus 2% corn oil for 3 wk. A single dose of [3H]aflatoxin B1 [(3H]AFB1) was administered ip and the biliary excretion of aflatoxin metabolites and the binding of 3H to nucleic acids were studied. In other experiments the in vitro metabolism of AFB1 by liver postmitochondrial supernatants prepared from rats fed the different sources of dietary fat was determined. The major nonextractable aqueous metabolite of AFB1 was the aflatoxin B1-glutathione conjugate (AFB1-GSH). Variation in the source of dietary fat did not affect production of the conjugate, nor was in vivo binding of AFB1 to nucleic acids affected. Aflatoxin P1 ( AFP1 )--mostly conjugated--and aflatoxin M1 (AFM1) were also identified in the bile, and the quantities of these metabolites produced were unaffected by the dietary treatments. The metabolites recovered in the in vitro study included aflatoxins Q1, P1 and M1. The corn oil diet produced a higher microsomal cytochrome P-450 level than the coconut oil diet. Associated with the higher level of cytochrome P-450 was increased in vitro conversion of AFB1 to AFQ1 and AFM1, but not to AFP1 . The in vitro production of aqueous metabolites and the covalent binding of metabolites to protein was unaffected by the dietary treatments. The results of the in vivo and in vitro studies suggest that the formation of the putative carcinogenic metabolite, AFB1-epoxide, which undergoes detoxification through glutathione conjugation, is not affected by the type of dietary fat. These observations further suggest that dietary fat, in particular unsaturated fat, affects AFB1 carcinogenesis through a mechanism other than by alteration of the metabolic activation of AFB1.

Aflatoxin B1↗

PubMed1984

Urinary excretion of thiol conjugates of aflatoxin B1 in rats and hamsters.

After intraperitoneal injection of [3H]aflatoxin B1 in rats and hamsters, 24-h urinary excretion of aflatoxin B1 metabolites was examined in these species. Total excretion was 10-15% of the injected dose with hamster excreting 50% more than the rat. In both species, 60% of the total excretion was due to glucuronide and sulfate conjugates of hydroxy metabolites. Striking differences were observed in the excretion of both aflatoxin B1-diol and various thiol conjugates. Aflatoxin B1-glutathione and aflatoxin B1-cysteinylglycine were major thiol conjugates in rats and hamsters, respectively. An unknown metabolite believed to be mercapturic acid (N-acetylcysteine conjugate) of aflatoxin B1 was excreted by both species, hamster excreting twice as much as the rat.

Acetylcysteine↗

PubMed1986

Aflatoxin B1 transport in rat blood plasma. Binding to albumin in vivo and in vitro and spectrofluorimetric studies into the nature of the interaction.

Binding of [3H]aflatoxin B1 to rat plasma was investigated in vivo and in vitro. Column chromatographic and polyacrylamide gel electrophoretic analyses clearly demonstrated that aflatoxin B1 bound primarily plasma albumin. Very little binding activity was shown by other plasma proteins. Spectrofluorimetric studies were undertaken to gain some insight into the nature of the aflatoxin-albumin interaction. Quenching of the lone tryptophan fluorescence intensity upon aflatoxin binding was due, at least in part, to a ligand-induced conformational change in the albumin molecule. Aflatoxin B1 binds an apolar site with an association constant of 30 mM-1 at pH 7.4 and 20 degrees C. Neither charcoal treatment of rat albumin nor the presence of 0.15 M NaCl had any significant effect on the interaction. The association constant was pH-dependent, increasing about 1.7-fold as the pH increased from 6.1 to 8.4. This pH dependence is ascribed to a pH-induced conformational change in the albumin molecule. Thermodynamic studies indicated that the aflatoxin-albumin interaction was exothermic (delta H = -29.3 kJ X mol-1), with a delta S value of -13.8 J X mol-1 X K-1.

Aflatoxin B1↗

PubMed1990

NMR-studies of carcinogen reactions with DNA: ethylene dibromide and aflatoxin B1.

Two examples are described of the use of NMR spectroscopy to study the modification of DNA structure by carcinogens. The reaction of ethylene dibromide involves initial conjugation with glutathione, catalysed by glutathione S-transferase. Reaction of this adduct with DNA occurs at N7 of guanine. Through the use of stereospecifically 1,2-dideuteriated ethylene dibromide, the mechanism of reaction has been shown to involve an odd number, i.e. three, of SN2 inversions. Correlation spectra (COSY) were employed to analyse reaction stereochemistry. The relative configuration of the deuterium atoms in the products was initially assigned by 1H nuclear Overhauser effect (NOE) difference spectra and then confirmed by an independent synthesis of stereospecifically dideuteriated glutathione-guanine adducts. The second example involves reaction of the epoxide of aflatoxin B1 with DNA to form covalent adducts at N7 of guanine. Adduct formation was found to enhance duplex stability. Chemical shift changes for aflatoxin protons in the covalent adduct when compared with those for aflatoxin B1 non-covalently associated with DNA suggest that covalently linked aflatoxin is intercalated. NOEs confirm that the aflatoxin moiety is intercalated and show that it is on the 5' side of the guanine. This geometry leads to d(ATCGAT)2 forming an adduct in which only one chain has been modified by aflatoxin, while d(ATGCAT)2 forms a complex in which both chains have been modified.

Aflatoxin B1↗

PubMed2004

Aflatoxins in pozol, a nixtamalized, maize-based food.

To determine whether pozol, a nixtamalized maize-based food was contaminated with aflatoxins, samples of non-fermented pozol were collected during the period November 2002 to April 2003 from local markets at Comitan in Chiapas, Mexico. The samples were analyzed for the presence of aflatoxins. Nineteen out of one hundred and eleven samples were contaminated with aflatoxin B2 (AFB2) and traces of aflatoxin B1 (AFB1). The percentage of samples contaminated with AFB2 in pozol prepared with white maize was 5.4%. Pozol mixed with toasted cacao paste had a contamination rate of 41.5%. No aflatoxins were detected in pozol prepared with yellow maize. It was found that only 1 of 19 contaminated samples had aflatoxin concentrations above 20 ppb.

Aflatoxin B1↗

PubMed1982

Inactivation of aflatoxin B1 mutagenicity by thiols.

The mutagenicity of aflatoxin B1 to Salmonella typhimurium strain TA98 decreased rapidly upon exposure of aflatoxin B1 to various thiols in aqueous solution. Mutagenic activity was reduced to control values within 24 hr with N-acetyl-L-cysteine (NAC), N-2-mercaptopropionylglycine (MPG), mercaptoethanol, reduced glutathione or mercaptopropionic acid at pH values near 4. Mercaptoacetic acid, mercaptosuccinic acid, cysteine, acetyl-D,L-homocysteine thiolactone, cysteine methyl ester, D-penicillamine and beta-mercaptoethylamine were less effective. Relatively high thiol concentrations (greater than or equal to 0 . 25 M) were required to achieve complete inactivation within 24 hr with the thiols tested. The inactivation rate was strongly dependent on thiol concentration and pH, but was relatively independent of the aflatoxin concentration under the conditions examined. With MPG and NAC reaction rates were much slower at neutral pH values than at pH's between 3 and 4. HPLC and thin-layer chromatographic examination of aflatoxin B1 solutions partially inactivated with NAC revealed the formation of a new product at a rate that correlated with the disappearance of aflatoxin B1 and the loss of mutagenic activity. This reaction product has not yet been identified, but the evidence suggests that it is the product of an addition of the thiol at the difuran region of the aflatoxin.

Aflatoxin B1↗

PubMed1995

Aflatoxin contamination of sorghum seeds during storage under controlled conditions.

Aflatoxins were estimated in two sorghum seed varieties (CSH-9 and AJ 140) collected in India and stored at three different temperature and humidity levels showed 20 degrees C and 73.5% relative humidity (RH) to be safe storage conditions. A maximum aflatoxin level was observed at 31 degrees C and 81.0% RH. Though the fungus grew well at 40 degrees C and all the humidity levels tested aflatoxin production was comparatively lower but reached hazardous level after 5 months of storage. Though all four aflatoxins were detected in both the seed samples, aflatoxin B1 and aflatoxin G1 were most predominant.

Aflatoxin B1↗