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PubMed1998

Detoxification of aflatoxin B1 by enzymes isolated from Armillariella tabescens.

Detoxification of aflatoxin B1 (AFB1) by Armillariella tabescens multienzyme, which was isolated from mycelium pellets of A. tabescens, was confirmed by thin-layer chromatography (TLC) and rat assay. The results of toxicology and pathology studies showed that toxicity of AFB1 was minimized after treatment with A. tabescens multienzyme. The result of the Ames test indicated that the mutagenic activity of multienzyme-treated AFB1 was greatly reduced (or inactivated) compared with that of untreated controls. TLC determinations showed that AFB1 at an initial concentration of 16 microM was completely detoxified (100%) by the fungal multienzyme. The infrared spectrum suggests that the multienzyme is responsible for opening the difuran ring of AFB1.

Aflatoxin B1↗
PubMed1986

Changes in liver polyamines due to aflatoxin B1.

Changes in liver polyamines of rats and mice of both sexes injected with aflatoxin B1 (AFB1) were determined. AFB1 significantly enhanced liver polyamines of both susceptible and resistant animals, viz. rats and mice, respectively. Sex appears to have little influence on AFB1-mediated stimulation of liver polyamine levels. AFB1 significantly reduced liver polyamine in growing rats reflecting the inhibitory effect of this carcinogen on induced polyamine synthesis.

Aflatoxin B1↗
PubMedDate not supplied

Preparation of aflatoxin B1 8,9-epoxide using m-chloroperbenzoic acid.

Aflatoxin B1 is a potent carcinogen which requires activation in order to react with DNA. The exo-8,9-epoxide is putatively the active form although it has thus far eluded direct detection in biological systems. This laboratory has reported a synthesis of the epoxide using dimethyldioxirane as the oxidant [(1988) J. Am. Chem. Soc. 110, 7929-7931]. A new, very convenient synthesis is described herein in which m-chloroperbenzoic acid is used as the oxidant in a two-phase system. The reaction is carried out in CH2Cl2 in contact with an aqueous phosphate buffer (pH 7.2) to remove the byproduct m-chlorobenzoic acid, which would otherwise react with the epoxide. Excess m-chloroperbenzoic acid is removed with aqueous sodium thiosulfate.

Aflatoxin B1↗
PubMed1999

Aflatoxin B1 is an inhibitor of cyclic nucleotide phosphodiesterase activity.

Aflatoxin B1 (AFB1) action on cyclic nucleotide phosphodiesterase (PDE) activity has been tested on tissue extracts of various organs. In the presence of 100 microM AFB1 a significant inhibition of cAMP and cGMP hydrolytic activity is observed in all tested tissue extracts. However, cGMP hydrolytic activity appears more sensitive to AFB1 inhibition than cAMP hydrolytic activity and a considerably higher inhibition is observed in lung and spleen, than in liver, brain, kidney, and heart. When cGMP is used as substrate, the inhibitory response reaches 72% in lung and spleen extracts. We have also tested AFB1 effects on lung and liver PDE activity peaks separated by DEAE-cellulose chromatography. These data confirm the poor sensitivity to the toxin of all PDE activities present in liver, while the lung peak (where PDE V in present) shows a higher sensitivity to AFB1. In order to establish whether PDE V is in fact more sensitive to AFB1, we have used mouse neuroblastoma cells, in which cGMP hydrolytic activity has been shown to be due to PDE V only. In this case, the calculated IC50 is 24 microM and Dixon plot analysis shows a competitive inhibitory effect with a Ki of 16.7 microM. We have also used aflatoxin B2 and M2, and they proved to be much less effective than AFB1: AFB2 inhibits PDE V with an IC50 of 117 microM, while AFM2 does not show any effect. These results provide the first evidence of a competitive inhibition of AFB1 on an enzymatic activity and suggest that an alteration of cellular cyclic nucleotide levels may play a role in the mechanism of aflatoxin action.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1994

Micronuclei, chromosomal aberrations and aflatoxin-albumin adducts in experimental animals after exposure to aflatoxin B1.

Rats and mice differ markedly in sensitivity to aflatoxin B1 (AFB1) hepatocarcinogenicity, the former being sensitive and the latter resistant. Animals were treated with single doses of different concentrations of AFB1, between 0.01 and 1.0 microgram AFB1/g body weight. The frequency of chromosomal aberrations and micronuclei in the bone marrow was measured and compared to the level of AFB1 bound covalently to albumin in the peripheral blood. Both chromosomal aberrations and micronuclei were significantly increased in treated rats compared to the control group at doses above 0.1 microgram/g. In contrast, in mice, a slight increase in chromosome aberrations was seen in the highest dose group (1.0 microgram/g) but no increase in micronuclei was observed at any of the doses. The level of chromosomal aberrations was about 10 times higher in rats than in mice at the highest dose of AFB1. AFB1-albumin (AF-alb) adducts did not show a strong dose-response increase after treatment in mice, whereas in rats the levels increased linearly with dose of AFB1 and there were strong correlations at the individual rat level with both chromosomal aberrations (r = 0.92; p < 0.0001) and micronucleus frequency (r = 0.86; p < 0.0001). These data suggest that the AF-alb may reflect the level of genetic alteration resulting from the initial binding of this carcinogen to cellular DNA. Therefore, this adduct used as a biomarker in studies of human exposure to aflatoxin may provide information not only on exposure but also on the risk of genetic alterations consequent to that exposure.

Aflatoxin B1↗
PubMed1999

A comparative evaluation of aflatoxin B1 genotoxicity in fish models using the Comet assay.

Aflatoxin B1 (AFB1) is classified as a Group I hepatocarcinogen in humans by the International Agency for Research on Cancer (IARC). The alkaline Comet assay is a simple and rapid method by which DNA damage can be demonstrated as a function of tail moment. The present work is the first to evaluate the genotoxicity of AFB1 in fish using the Comet assay. Two different species of fish were selected as models due to previously established sensitivity to AFB1: rainbow trout (sensitive) and channel catfish (resistant). Fish were i.p. injected with 0.5 mg AFB1/1 ml DMSO/1 kg body weight. The Comet assay was performed after 4 and 24 h on whole blood, liver, and kidney cells of both species. Trout blood and kidney tissue tested displayed significant (p < 0.05) and extensive DNA damage (shown by increased tail moment) after 4 h which then decreased by 24 h. In liver cells, damage progressively increased over time. Conversely, similarly treated catfish showed no elevation in DNA damage over controls at the same doses. These results suggest that the Comet assay is a useful tool for monitoring the genotoxicity of mycotoxins such as AFB1 and for evaluating organ specific effects of these agents in different species.

Aflatoxin B1↗
PubMed1986

Tissue distribution and hepatic ultrastructural effects of aflatoxin B1 in Japanese quail.

Fertile, Japanese quail eggs were injected with graded levels of aflatoxin B1 (AFB1) dissolved in ethanol. Hatchability varied inversely with the quantity of AFB1 administered. The generated quail were utilized in studies of AFB1 distribution and its effects upon hepatic ultrastructure. Putative AFB1 was detected within the livers of two quail 6 h after dosing, although the AFB1 distribution was inconsistent between the individuals. Electron microscopy revealed that liver parenchymal cells from AFB1-treated exhibited mitochondrial pleomorphism 6 h after dosing, a rare observation in control tissue.

Aflatoxin B1↗
PubMed1994

Hepatic and extrahepatic bioactivation and GSH conjugation of aflatoxin B1 in sheep.

Whole-body autoradiography of [3H]aflatoxin B1 ([3H]AFB1) in lamb showed a localization of bound labelling, in addition to the liver, in the nasal olfactory and respiratory mucosa, in the mucosa of the nasopharynx, pharynx, oesophagus, larynx, trachea, bronchi and bronchioles and in the palpebral and bulbar conjunctiva. Microautoradiography revealed that the bound material was confined to specific cell types in extrahepatic tissues. Whole-body autoradiography also showed a labelling of pigmented tissues (such as the eye melanin), which can be ascribed to a melanin affinity of AFB1. In vivo experiments, performed with microsomal preparations of tissues from ewe and lamb showed that several of the extrahepatic tissues were more efficient than the liver in forming DNA-bound AFB1 metabolites. The nasal olfactory mucosa was by far the most effective tissue in this respect. AFB1 induced a high number of gene mutations in Salmonella typhimurium TA100 when incubated with supernatant preparations (9000 g) of the nasal olfactory mucosa, whereas incubations with preparations of the liver resulted in a lower effect. It has been reported that AFB1 can induce nasal tumours in sheep. When microsomal preparations of various tissues were incubated in the presence of reduced glutathione (GSH), but without any addition of cytosolic glutathione-S-transferase (GST), a drastic decrease in the AFB1-DNA binding was seen. Analyses of the water-soluble metabolites formed in the microsomal incubations supplemented with GSH showed fluorescent and ninhydrin-positive metabolites that were not present in the absence of GSH. These results indicate that sheep tissues have intrinsic microsomal GST or cytosolic GSTs associated with the microsomal fraction with a high capacity to catalyse the conjugation of bioactivated AFB1 to GSH. The results of the present study show that several extrahepatic tissues of sheep have a potent capacity to bioactivate AFB1 and also a high capacity to GSH conjugate the bioactivated AFB1.

Aflatoxin B1↗
PubMed1990

Dose and time dependence of chromosomal aberration yields of bone marrow cells in male Chinese hamsters after a single i.p. injection of aflatoxin B1.

The frequency of chromosomal aberrations in bone marrow cells, after a single i.p. aflatoxin B1 (AFB1) dose, was examined in male Chinese hamsters (Cricetulus griseus). There was a significant increase in aberrant cells within 5 days of administration of a dose of 0.1 micrograms-5 mg AFB1/kg, and on the 36th day. After a single dose of 5 mg AFB1/kg the enhanced frequency of aberrant cells was monitored up to day 104 with no sign of a decrease to control level. The results indicate that the minimum mutagenic effect of an AFB1 dose in this system is 0.1 micrograms/kg. Attention is drawn to the long-term presence of chromosomal aberrations even after a single i.p. exposure to AFB1.

Aflatoxin B1↗
PubMed1987

Effects of mycotoxins in cultured kidney cells: cytotoxicity of aflatoxin B1 in Madin-Darby and primary fetal bovine kidney cells.

The cytotoxicity of aflatoxin B1, a fungal metabolite and an important food contaminant, was evaluated in an established cell line, Madin-Darby bovine kidney (MDBK) cells, and in primary fetal bovine kidney (PFBK) cells. Cells were grown in monolayers and treated with media containing AFB1 for 24 hr. Both culture systems were sensitive to the chemical; the PFBK cultures were approximately four times more susceptible to the cytotoxic effect. Cell multiplication decreased in both systems in long-term cultures. Adherence of MDBK cells was only slightly reduced at the toxic concentrations of the chemical. Electron microscopy revealed condensation of chromatin, separation of nuclei from the cytoplasm, cytoplasmic vacuolization, and loss of surface microvilli. Results indicated differential sensitivity of the two culture systems.

Aflatoxin B1↗
PubMed1991

Ultrastructure of hepatocellular neoplasms in aflatoxin B1 (AFB1)-initiated rainbow trout (Oncorhynchus mykiss).

The fine structure of hepatocellular neoplasms from aflatoxin B1 (AFB1)-initiated rainbow trout was studied by transmission electron microscopy. Large, usually uniform hepatic nuclei, large nucleoli, abundant, dilated rough-surfaced endoplasmic reticulum, and reduced glycogen storage were common findings in both hepatocellular adenomas and hepatocellular carcinomas. In addition, the presence of poorly developed microvilli in the space of Disse and in bile canaliculi, the occurrence of few or no bile preductule cells and a striking increase in the size and number of intercellular spaces characterized hepatocellular carcinomas. The three latter characteristics of hepatocellular carcinomas suggest loss of inter-relationships between hepatocytes and the microvascular system (sinusoids), between hepatocytes and the biliary system, and between individual hepatocytes, respectively. With respect to these parameters, adenomas were more similar to normal liver than to carcinomas.

Adenoma↗
PubMed1986

Increased UDP-glucuronyltransferase and gamma-glutamyltranspeptidase in enzyme-altered rat liver lesions produced by low doses of aflatoxin B1.

Preneoplastic liver lesions were produced in female Wistar rats by low doses of aflatoxin B1 (Model 1: administration of 37.5 micrograms/kg 12 and 24 h after partial hepatectomy; Model 2: continuous application of 3.5 micrograms/kg in tap water daily for 28 days with partial hepatectomy after 14 days. The animals then received sodium phenobarbital, 0.1% in tap water, for 180 to 400 days). In both models numerous altered hepatic foci (AHF) and hyperplastic nodules (HN) were detected enzyme histochemically by their negative ATPase and positive gamma-glutamyltranspeptidase reactions. Immunohistochemically these lesions were also UDP-glucuronyltransferase positive. Increased UDP-glucuronyltransferase adds to permanent alterations of a number of drug metabolizing enzymes observed in a variety of different tumor models. These alterations are responsible for the toxin-resistant phenotype (Faber 1984b). Increased gamma-glutamyltranspeptidase was detected both enzyme histochemically and immunohistochemically; whereas gamma-glutamyltranspeptidase activity was present in both AHF/HN and in periportal areas by enzyme histochemistry, the immunohistochemical method selectively stained gamma-glutamyltranspeptidase in AHF and HN. Immunohistochemically detectable UDP-glucuronyltransferase and gamma-glutamyltranspeptidase are markers of putative precancerous liver lesions which may be useful in the analysis of the prestages of liver carcinogenesis.

Aflatoxin B1↗
PubMed1988

Developmental toxicity of aflatoxin B1 in the rodent embryo in vitro: contribution of exogenous biotransformation systems to toxicity.

Aflatoxin B1 (AFB1) is a known carcinogen and developmental toxin in various species of mammals, birds, amphibians, and fish. AFB1 requires metabolic activation (biotransformation) to the 2,3-epoxide metabolite for carcinogenicity; however, it is unknown if biotransformation is a prerequisite for AFB1 embryotoxicity. Cultured day 10 rat embryos were exposed to AFB1 alone and AFB1 in the presence of cofactors and hepatic S9 fractions from adult male rats induced with either phenobarbital or 3-methylcholanthrene. Under these different culture conditions qualitatively similar patterns of malformation were seen in all embryos exposed to AFB1. At culture concentrations of 15 microM or greater, AFB1 produced abnormalities in neural tube development in a concentration-dependent manner. The presence of hepatic S9 fractions had no effect on the ability of AFB1 to produce dysmorphogenesis in vitro or on the spectrum of malformations elicited. However, the addition of hepatic S9 fractions did greatly enhance the embryolethality of AFB1. This enhancement was greater with phenobarbital- than 3-methylcholanthrene-preinduced hepatic S9 fractions. Our results suggest that separate chemical mediators may be responsible for the embryolethal and dysmorphogenic effects of AFB1 observed in day 10 rat embryos in vitro. We found that the embryolethality of AFB1, but not the dysmorphogenicity, could be greatly modulated by exogenous biotransformation.

Abnormalities, Drug-Induced↗
PubMed1994

Metabolism of benzo(a)pyrene, dimethylbenzanthracene and aflatoxin B1 by camel liver microsomes.

The ability of camel liver microsomes to metabolise a range of common environmental carcinogens including benzo(a)pyrene, dimethylbenzanthracene and aflatoxin B1 has been investigated. The camel liver has shown the ability to metabolise benzo(a)pyrene, dimethylbenzanthracene and aflatoxin B1 to a number of metabolites. The major metabolites of benzo(a)pyrene produced by camel liver enzymes were identified as its mono-hydroxy derivatives and suggest that the metabolic detoxification pathways of carcinogen metabolism are predominant in this species. Benzo(a)pyrene metabolising activity in camel liver required NADPH and was inhibited by CO and alpha-naphthoflavone suggesting the involvement of cytochrome P450 in the metabolism of this carcinogen by camel liver. The cytochrome P450-dependent metabolism of carcinogen and other specific substrates such as ethoxyresorufin and ethoxycoumarin, by camel liver enzymes, was about 50% higher than that of rat liver enzymes. The cytochrome P450-dependent metabolism of a variety of carcinogenic and other substrates by camel liver demonstrated that there are multiple forms of cytochrome P450 enzymes involved in the metabolism of a wide array of xenobiotics and pollutants.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1987

Aflatoxin B1 activation to a plasmid mutagen by a chemical model of cytochrome P-450.

Aflatoxin B1 (AFB1) was oxidised by a chemical model of cytochrome P-450 and the products obtained analysed by reversed-phase hplc. The oxidation system employs a water-insoluble iron(III)porphyrin catalyst (tetraphenylporphinatoiron(III) chloride; FeTPPCl) and an oxygen donor, iodosylbenzene (PhIO). The two AFB1 products obtained from this reaction were derived by initial oxidation across the 8-9 double bond of AFB1 and subsequent breakdown of AFB1-8,9-epoxide, the compound postulated to be the ultimate carcinogenic and mutagenic derivative of AFB1. Oxidation of AFB1 by the porphyrin-catalysed system in the presence of calf-thymus DNA, resulted in the formation of AFB1-DNA adducts identical to those formed in vivo and in vitro after liver mono-oxygenase activation. The chemical model system was therefore used on a microscale to react AFB1 with plasmid pHR1800, a plasmid containing the genes for beta-lactamase (amp-r) and galactokinase (galK). AFB1-modified plasmid DNA was then transformed into E. coli AB1886 (uvrA-) and the effects of the AFB1-DNA adducts on plasmid survival and the ability of pHR1800-transformed bacteria to metabolise galactose, were then studied. The results showed an AFB1 dose-dependent decrease in plasmid survival and increase in the mutation frequency of the galK gene only when the complete oxidation system was used to generate the reactive AFB1 metabolite.

Aflatoxin B1↗
PubMed1986

Induction of DNA single-strand breaks and DNA synthesis inhibition by patulin, ochratoxin A, citrinin, and aflatoxin B1 in cell lines CHO and AWRF.

Four mycotoxins, patulin, ochratoxin A, citrinin, and aflatoxin B1 (AFB1), were compared for their cytotoxicity, DNA synthesis inhibition and DNA damage in CHO and AWRF cells. The concentrations causing a 50% inhibition of colony formation in CHO cells were 0.07, 33, 31, and 10 micrograms/ml, respectively, for patulin, ochratoxin A, citrinin, and AFB1. Values obtained for AWRF cells were 0.011, 6.4, 6.7, and 0.15 micrograms/ml, respectively. Patulin strongly inhibited DNA synthesis in both CHO and AWRF cells, at concentrations over 4 micrograms/ml. Ochratoxin A and citrinin elicited mild inhibition of DNA synthesis (up to 20%) at concentrations greater than 50 micrograms/ml. AFB1 at concentrations over 5 micrograms/ml strongly inhibited DNA synthesis in AWRF cells but stimulated DNA synthesis in CHO cells. In accordance with these findings, AFB1 induced single-strand breaks in the DNA of AWRF cells only. Patulin induced about the same levels of DNA breaks in both types of cells, at concentrations greater than 2 micrograms/ml. Citrinin and ochratoxin A produced DNA breaks in CHO cells, at a very high concentration of 200 micrograms/ml. The number of breaks induced in AWRF cells was not statistically significant. The results suggest that the different effects of AFB1 on CHO and AWRF cells are due to the different ability of these cells to metabolize AFB1 to the ultimate carcinogen AFB1-8,9-oxide by microsomal cytochrome P-450-dependent oxygenases. The effects of the other mycotoxins not requiring the metabolic activation were comparable for both cell types.

Aflatoxin B1↗
PubMed1984

Effect of dose on the inhibition of carcinogenesis/mutagenesis by Aroclor 1254 in rainbow trout fed aflatoxin B1.

Prior studies have shown that Aroclor 1254 (PCB) differentially alters the incidence of aflatoxin B1 (AFB1) induced hepatocellular carcinomas in trout, depending upon the time of PCB administration relative to AFB1 exposure (Shelton et al., 1983). When fed simultaneously with AFB1, PCB inhibits carcinoma incidence. We investigated the effect of AFB1 and PCB dose on this inhibition. Duplicate tanks of 100 rainbow trout were fed AFB1 at concentrations of 1, 4, or 8 ppb, either with or without the addition of 50 ppm PCB. Other groups were fed 4 ppb AFB1 + 5 ppm PCB, 50 ppm PCB alone, or control diet alone. After 9 and 12 mo, 40 and 60 fish per tank, respectively, were sampled to determine the incidence of liver tumors. The results show a parallel inhibition of the AFB1-tumor dose-response curve by the presence of 50 ppm PCB. Fish fed 4 ppb AFB1 + 5 ppm PCB showed slight inhibition in response when compared with 4ppb AFB1 alone. Also, livers from fish fed 50 ppm PCB were used to prepare S20 for use in the Salmonella mutagenesis assay. These livers were less efficient in converting AFB1 to a mutagen, when compared to control S20. The AFB1-mutagenesis dose-response curve was again shifted parallel to the right of the curve generated using control S20. These results suggest that the inhibitory action is at least partly at the level of carcinogen activation. The finding of parallel, as opposed to proportional, inhibition with varying carcinogen exposure for certain classes of inhibitors may have important implications for inhibition of environmental carcinogenesis at low levels of carcinogen exposure.

Aflatoxin B1↗
PubMed2001

Occurrence of aflatoxins B1, B2, G1 and G2 in cooked food components of whole meals marketed in fast food outlets of the city of São Paulo, SP, Brazil.

Samples of cooked components of regular meals served at fast food outlets of the city of São Paulo, Brazil were analysed for aflatoxins B1, B2, G1 and G2. The 322 samples were composed of prepared traditional Brazilian and ethnic foods in which aflatoxins might be present. Thin-layer chromatography was used for separation of the compounds and their determination was achieved by both long wave UV light and fluorodensitometry. Aflatoxins were detected in 30 samples (9.31% of the total) in a range of 2.80 to 1323 ng/g for B1 + B2 + G1 + G2 with 90th percentiles of 158 (B1 + G1) and 258 (B1 + B2 + G1 + G2). Aflatoxin B1 was detected in all contaminated samples. The contamination levels and frequency of aflatoxins B1 and G1 in positive samples above 20 ng/g in this study are high, indicating that there is a certain degree of exposure of the population to the carcinogenic aflatoxin.

Aflatoxin B1↗