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PubMed1982

Metabolism and activation of aflatoxin B1 by reconstituted cytochrome P-450 system of rat liver.

Metabolism and activation of aflatoxin B1, a potent hepatocarcinogenic and mutagenic mycotoxin of Aspergillus flavus, were investigated in the reconstituted enzyme system composed of purified NADPH-cytochrome P-450 reductase and cytochrome P-450 or P-448 of rat liver. The aflatoxin M1 formation was strictly mediated by P-448 purified from the liver microsomes of polychlorobiphenyl- and 3-methylcholanthrene-treated rats, while the aflatoxin Q1 formation, as well as the binding of DNA, were catalyzed by both P-450 and P448. Differences between the kinetic data on metabolism and activation of aflatoxin B1 obtained with the reconstituted cytochrome systems and those obtained with the microsomal and nuclear systems were discussed, and the significance of these biochemical data in the in vivo carcinogenicity of aflatoxin B1 was evaluated.

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PubMed1977

Aflatoxin B1, a selective inhibitor of DNA synthesis in mammalian cells.

Aflatoxin B1 in concentrations between 0.01 and 0.1 microgram/ml inhibits DNA synthesis in African green monkey cells in culture, but has little effect on RNA synthesis and no effect on protein synthesis. The drug even at concentrations up to 1.0 microgram/ml does not interfere with DNA repair promoted by ultraviolet irradiation nor does it induce DNA repair. The inhibition of DNA synthesis attains maximum values 3 h after addition of aflatoxin B1 and is irreversible upon removal of the drug. Profiles of pulselabeled DNA sedimented in alkaline sucrose gradients indicate that aflatoxin B1 blocks initiation of replication rather than elongation.

Aflatoxins↗

PubMed1987

Strain differences in the metabolic activation of aflatoxin B1 in the rat.

It has been reported that female Fischer rats are much more susceptible to the hepatocarcinogenic effects of aflatoxin B1 than female DA rats. Female Fischer rats are approximately twice as active as female DA rats in producing adducts of aflatoxin B1 with DNA in vivo, in freshly isolated hepatocytes and with hepatic microsomal fractions. There was no difference between the hepatic microsomal fractions from Fischer and DA rats in the production of adducts between aflatoxin B1 and microsomal protein. The difference between the strains in the formation of adducts with DNA was not due to either the activity of glutathione S-transferases or to the selective destruction of cytochrome P-450 in the DA strain. None of the differences reported here was of sufficient magnitude to explain the difference in susceptibility of the rat strains to the hepatocarcinogenic effects of aflatoxin B1.

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PubMed1981

Effect on calves of barley naturally contaminated with ochratoxin A and groundnut meal contaminated with low concentrations of aflatoxin B1.

Four groups of six 12-week-old male Friesian calves were fed diets containing 390 to 540 microgram ochratoxin A per kg, 320 to 500 microgram ochratoxin A plus 12 to 13 microgram aflatoxin B1 per kg, 10 to 13 microgram aflatoxin B1 per kg, or a control diet containing neither toxin. At the end of the 87-day experiment there was no evidence of kidney or liver damage in any group of animals as judged by serial plasma and urine enzyme assays, haematological examinations including the assay of blood coagulation factors, gross appearance at autopsy or histopathological assessment at the light microscopic level. Nor was there any significant alteration in serum IgA, IgM, IgG1 and IgG2 levels or in titres to environmental bacterial and viral antigens. Trace amounts of ochratoxin A were detected in kidneys of five out of the 12 calves exposed to this toxin but all 12 kidneys contained residues of the metabolite ochratoxin alpha (less than 5 to 10 microgram/kg). Traces of aflatoxin B1 and M1 were detected in the liver of one of the 12 calves exposed to aflatoxin B1 but nine kidneys contained the metabolite aflatoxin M1 (less than 0.01 to 0.03 microgram/kg). There was no evidence of interaction between the two toxins.

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PubMed1990

Chemical and physical properties of the major serum albumin adduct of aflatoxin B1 and their implications for the quantification in biological samples.

Aflatoxin B1 (AFB1) is a potent carcinogen. It reacts with liver DNA and serum albumin in a dose-dependent manner. Serum albumin adducts of aflatoxins have been used for exposure assessment. The immunological methods used so far do not differentiate between the different adducts of AFB1 and of AFG1. In order to establish an analytical method to measure one specific AFB1 adduct, we investigated the structure and the chemistry of the major serum albumin adduct of aflatoxin B1 (lysine-AFB1). 13C-NMR, 1H-NMR, UV, IR, fluorescence and MS spectra of lysine-AFB1 (8-[N-(2-amino-hexanoyl-6-yl)-5-oxo-3-pyrrolin-3-yl]-7-hydroxy-5- methoxycyclopentenone[2.3-c]coumarin) were recorded and discussed. The quantification of lysine-AFB1 was demonstrated in biological samples. Serum albumin was digested with pronase and analysed by HPLC with a fluorimeter as detector. The detection limit found for lysine-AFB1 was 20 fmol.

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PubMed1992

Extrahepatic disposition of 3H-aflatoxin B1 in the rainbow trout (Oncorhynchus mykiss).

Whole-body autoradiography in rainbow trout (Oncorhynchus mykiss) after oral and intravenous administration of 3H-labelled aflatoxin B1 showed labelling of several extrahepatic tissues, such as the uveal melanin and the vitreous humour of the eyes, the trunk and head kidney, the olfactory rosettes and the pyloric caecae. Liquid chromatography of extracts of the vitreous humour showed that unmetabolized 3H-AFB1 was the main labelled material present at this site. Liquid chromatography of extracts of the uveal melanin showed presence of aflatoxicol and aflatoxin B1 in proportions of about 3:1. The binding to the pigment is probably due to a hydrophobic type of interaction with the melanin. Microautoradiography showed that melanin-containing cells in the trunk and head kidney and in the olfactory rosettes also accumulated high amounts of radioactivity. In the trunk kidney there was, in addition, a labelling of the second segment of the proximal tubules and of the distal tubules and the collecting ducts. Studies in vitro with microsomal and 12,000 x g supernatant preparations of the trunk kidney showed formation of DNA- and protein-bound metabolites from the aflatoxin B1. It is probable that the bioactivation of the aflatoxin B1 is confined to the cytoplasm of the cells, may be related to excretion and/or absorption processes. Microautoradiography of the olfactory rosettes, showed labelling of the sensory epithelium, but not the indifferent epithelium. A low formation of protein-bound aflatoxin B1-metabolites was found in incubations with microsomal preparations of this tissue. The same observation was made in incubations with microsomal preparations of the head kidney. In the pyloric caeca bound metabolites were observed in vivo at a level comparable to that found in the trunk kidney. Our results suggest that retention and metabolism in some extrahepatic tissues might be of importance as concerns the toxicologic potential of aflatoxin B1 in the rainbow trout.

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PubMed1978

Modification of hepatotoxic effects of aflatoxin B1 in rabbits by immunization.

Reduction of acute toxic effect of aflatoxin B1 was achieved by immunizing the rabbits with small amounts of bovine serum albumin-aflatoxin B1 conjugate. Rabbits after immunization showed lower mortality, near normal serum isocitric dehydrogenase activity, no abnormality in livers when challenged with a single dose of aflatoxin B1. The results suggest that immunization might be used prophylactically against aflatoxicosis.

Aflatoxins↗

PubMed1993

Repair of aflatoxin B1 DNA adducts by the UvrABC endonuclease of Escherichia coli.

The repair by UvrABC endonuclease of two major adducts formed by aflatoxin B1 in DNA was found to be similar. Aflatoxin epoxide was used to generate the aflatoxin B1.N7-guanine adduct which can convert to aflatoxin B1-formamidopyrimidine adduct. The reaction of the aflatoxin B1 epoxide with DNA follows pseudo-first order kinetics. The DNA sequence-specific relative reactivity of the epoxide is the same as previously observed for aflatoxin B1 activated by liver microsomes, therefore strongly reinforcing the notion that aflatoxin B1 reacts with DNA through the epoxide intermediate. For the majority of lesion sites, a high affinity protein-DNA complex was formed from the UvrA and the UvrB proteins with similar efficiency to both adducts, and to pyrimidine dimers, and then nicks the DNA when UvrC was added. The two incisions are at the eighth phosphodiester moiety 5' and the sixth phosphodiester moiety 3' of a modified guanine nucleotide. Both incisions appeared to be concerted. For some sites, the DNA sequence can alter the relative incision efficiency up to 15-fold. However, the majority of these AFB1 lesion structures in most DNA sequences are similar with respect to recognition by this nucleotide excision repair enzyme. Therefore the observation that the aflatoxin B1.N7-guanine lesion is removed rapidly, while the aflatoxin B1-formamidopyrimidine lesion persists in the mammalian cell may have other mechanistic explanations.

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PubMed1984

Toxicity of aflatoxin B1 in rat and mouse hepatocytes in vivo and in vitro.

The reported LD50 for the adult, male Fisher rat is 1.2 mg aflatoxin B1/kg body weight (i.p.); we have found that male C57BL/6 mice survive single doses of aflatoxin B1 as high as 60 mg/kg (i.p.). We have demonstrated a 1000-fold greater LC50 of aflatoxin B1 for primary mouse liver cell cultures from C57BL/6 male mice (3 X 10(-5) M) than for primary liver cells from F344 male rats (3 X 10(-8) M). In 4 h of exposure to a non-toxic dose (1 X 10(-9) M) of [3H]aflatoxin B1, cultured rat liver cells accumulated up to 5-fold higher concentrations of 3H label than did mouse liver cells. The difference in cell-associated counts was due largely to higher levels of aflatoxin B1 metabolites bound to macromolecules in the rat cells.

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PubMed1984

Failure of plant tissues to metabolize aflatoxin B1?

After exposure of peas and wheat kernels to aflatoxin B1 solutions the following aflatoxins could not be detected in seed extracts: aflatoxins M1, B2a, Q1, aflatoxicol and tetrahydrodeoxyaflatoxin B1.

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PubMed1976

Sex dependence of the metabolic activation in vitro of the mycohepatocarcinogen aflatoxin B1.

Using liver microsomes, metabolic activation of aflatoxin B1, determined by the formation of DNA- and protein-binding metabolites, was studied in an effort to elucidate the possible basis underlying sex differences in sensitivity of the male and female rat to aflatoxin B1. Male rats, which are more sensitive to AFB1, produced significantly higher amounts of these metabolites than female rats; castration of the male reduced the level to that of the female, whereas ovariectomy was without any effect.

Aflatoxins↗

PubMed1980

Aflatoxin B1 in dairy concentrates and other animal feedstuffs.

Over a period of 13 years 740 samples of various animal feedstuffs were analysed for the presence of aflatoxin B1. Nearly 500 were suspected of causing disease in farm animals but aflatoxin B1 could be detected in only 13.6 per cent of them. Groundnut meal samples nearly always contained the toxin but compounded feeds were contaminated to a varying extent. In particular, none could be detected in 62 poultry feeds. Where mycotoxicosis was suspected in dairy cattle, aflatoxin B1 was present at levels of more than 30 micrograms per kg in about 27 per cent of associated feed samples. In other dairy feeds (178 samples) this level of contamination was present in only about 9 per cent of samples. Concentrations of aflatoxin B1 likely to produce toxic effects (100 micrograms per kg and above) were present in about 4 per cent of suspect dairy concentrates but in 1 per cent or less of others. Contamination of dairy concentrates with aflatoxin B1 is usually at such a level that cows probably excrete the toxic metabolite aflatoxin M1 in milk at very low concentrations of 0.1 micrograms per litre or less.

Aflatoxins↗

PubMedDate not supplied

EC-collaborative study on the determination of aflatoxin B1 in animal feeding stuffs.

A collaborative study was conducted to test a method, proposed in the European Community (EC) as a candidate-official method for the determination of aflatoxin B1 in compounded feeding stuffs. The study was undertaken on behalf of the European Commission's Community Bureau of Reference (BCR). It involved 25 laboratories from 11 EC countries. The method, based on chloroform extraction and Sep-Pak Florisil and C18 cartridge clean-up, offered either reverse-phase high performance liquid chromatography (HPLC) with iodine post-column derivatization, or two-dimensional thin-layer chromatography (TLC) as determinative steps. In the study, 22 laboratories applied HPLC, three laboratories applied TLC. The study involved six unknown samples. These consisted of blind duplicate samples of compounded feeding stuff, with target concentrations of aflatoxin B1 at less than 2, 8 and and 14 micrograms/kg. Statistical analysis of the HPLC data was carried out according to ISO 5725. For the less than 2 micrograms/kg sample, all reported aflatoxin concentrations were less than 2 micrograms/kg. At the 8 and 14 micrograms/kg level (pooled), repeatability (r) and reproducibility (R), expressed as ratios, were 1.4 and 1.7 respectively, and within-laboratory and between-laboratory coefficients of variation were 11% and 18% respectively. The study revealed that admittance of daylight in the laboratory caused losses of aflatoxin B1 and must be avoided. New glassware coming into contact with aqueous solutions containing aflatoxin B1 was found to be a potential cause of loss of aflatoxin B1. The method has been recommended to the European Commission to be considered for adoption in EC regulations.

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PubMed1985

Quantitative and qualitative characterization of aflatoxin B1 adducts formed in vivo within the ribosomal RNA genes of rat liver DNA.

We have examined the time course and patterns of covalent aflatoxin B1:DNA adducts produced within the ribosomal RNA gene sequences isolated from the liver nuclear DNA of aflatoxin B1-treated animals. Liver nuclear DNA was initially enriched in ribosomal DNA by cesium salt density centrifugation, and incubated under alkaline conditions to stabilize bound aflatoxin B1-DNA moieties. Alkali-treated DNA was hybridized to 18S and 28S rRNA, and the RNA:DNA hybrids were recovered by cesium chloride centrifugation. Ribosomal DNA sequences within nuclear DNA were found to be preferential targets for aflatoxin B1 modification. Over a 12-h period after administration of 1-mg [3H]aflatoxin B1/kg dose ribosomal DNA contained 4 to 5 times more aflatoxin B1 residues per mg DNA than did total nuclear DNA. Aflatoxin B1 residues bound to ribosomal DNA were also found to be removed more rapidly than from total nuclear DNA by a factor of 5.7 over the 12-h period postdosing. Levels of the principal aflatoxin B1 adduct, 2,3-dihydro-3-hydroxy(N7-guanyl)aflatoxin B1, as well as the stable formamidopyrimidine derivatives of the parent adduct were also determined. Nuclear DNA isolates were heated to induce depurination of the principal N7-guanine adduct, and differences in adduct levels between alkali-treated (stabilized) and depurinated DNA samples were taken as an approximation of initial levels of this aflatoxin B1:DNA moiety in ribosomal isolates. No differences in the proportions of these aflatoxin B1:DNA adduct species were found in ribosomal as compared to total nuclear DNA, and we conclude that the preferential formation and removal of aflatoxin B1:DNA moieties within ribosomal DNA is not associated with a pattern of adducts qualitatively different from that in total nuclear DNA.

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PubMed1990

Biotransformation of aflatoxin B1 in rabbit lung and liver microsomes.

Aflatoxin B1 (AFB1) is a potent hepatotoxic and hepatocarcinogenic mycotoxin that requires bioactivation to AFB1-2,3-oxide for activity. In addition to epoxidation, microsomal monooxygenases biotransform AFB1 to the less toxic metabolites, aflatoxin M1 (AFM1) and aflatoxin Q1 (AFQ1). The lung is at risk from AFB1 both via inhalation and via the circulation. In the present study, we have characterized rabbit lung and liver microsomal AFB1-DNA binding (an index of AFB1-2,3-oxide formation), AFM1 formation and AFQ1 formation. Vmax values for AFB1-DNA binding were not different between lung and liver when expressed per mg microsomal protein (1.06 +/- 0.13 and 2.12 +/- 1.30 nmol/mg/h for lung and liver respectively), but lung values were greater than liver when expressed per nmol cytochrome P450 (3.64 +/- 0.31 and 1.29 +/- 0.70 nmol/nmol P450/h for lung and liver respectively). Km values for this reaction were not different between lung and liver. Vmax values for AFM1 formation in liver microsomes were greater than in lung when expressed per mg protein, but not when expressed per nmol P450. No differences were detected for the Km for AFM1 formation between lung and liver microsomes. For AFQ1 formation, no differences were detected between Vmax values of lung and liver, regardless of whether results were expressed per mg protein or per nmol P450, while the Km for AFQ1 formation was lower in liver. SKF-525A inhibited these reactions by 63-74% in lung microsomes and 90-96% in liver microsomes. These results indicate that the lung is capable of activating AFB1, and that rabbit lung microsomes contain high activity for this reaction. Furthermore, little AFM1 and AFQ1 are formed in lung microsomes, leading to minimal shunting of AFB1 from the activation pathway.

Aflatoxin B1↗

PubMed1982

Tissue, sex, and animal species specificity of aflatoxin B1 inhibition of nuclear RNA polymerase II activity.

Recent studies from this laboratory have shown that several chemical carcinogens, i.e., aflatoxin B1, N-OH-2-acetyl-aminofluorene, actinomycin D, and methylazoxymethanol acetate, when administered in vivo, have all produced a selective and dramatic inhibition of rat liver nuclear RNA polymerase II activity. To determine whether this inhibition is related to carcinogenesis, aflatoxin B1 is used as a model system to test tissue, sex, and animal species specificity that is known to be characteristic of carcinogenesis. The results show that aflatoxin B1 (3 mg/kg body weight, i.p., 2h) inhibits RNA polymerase II activity only in the target tissue, liver, and not in the non-target tissues, e.g., lung and brain. It inhibits liver RNA polymerase II activity preferentially in male over female rats, and has no effect on mouse liver RNA polymerase II activity. These results are in good agreement with the specificities of aflatoxin B1 carcinogenesis in the whole animal systems. Furthermore, with the four principal aflatoxins tested, the order of inhibitor effect on RNA polymerase II is: B1 greater than G1 greater than B2, G2. It is concluded, therefore, that the inhibition of RNA polymerase II activity and carcinogenesis are likely to be related and that it is theoretically sound to use this inhibition as a diagnostic tool to screen potential carcinogens.

Aflatoxin B1↗

PubMedDate not supplied

[Effect of qualitatively varying nutrition on several parameters of aflatoxin B1 metabolism and toxicokinetics].

The influence of qualitatively different nutrition (physiological and that with lysine, methionine, threonine and vitamins A, B, C deficiencies) on certain toxicokinetic parameters of 3H-aflatoxin B1, after single and multiple (every day, during 5 days) intraperitoneal injections of this agent in a dose of 25 micrograms/animal, was studied in two series of experiments on growing male WAG rats with the initial bw 40-50 g. It has been proved that the main parameters of aflatoxin B1 toxicokinetics depend on the injection multiplicity and the nutrition character. It has been established that the qualitative differences in the nutrition character essentially influence the stages of aflatoxin B1 distribution in the body, the sorption and metabolic transformation in the liver, enterohepatic recirculation, the rate and correlation of the main elimination routes. The nutrition character influences the level of persistence and cumulation of firmly bound aflatoxin B1 adducts in the liver and hepatocytic DNA. Possible mechanisms of such effects of different providing of the body with essential nutrients have been discussed. A conclusion has been made that the modifying effect of nutrition on the key stages of aflatoxin B1 toxicokinetics is realized, ultimately, in varying degree of the animal resistance to mutagenic and carcinogenic action of this agent.

Aflatoxin B1↗

PubMedDate not supplied

Detection and quantitation of aflatoxin B1 in orange juice by SOS-Chromotest.

A new method for the detection and quantitation of aflatoxin B1 in liquids is described. The method is based on the SOS Chromotest, in which damage caused by aflatoxin B1 to the DNA of suitably engineered E. coli induces beta-galactosidase. Aflatoxin B1 developing in orange juice inoculated with spores of Aspergillus parasiticus is detectable equally well by TLC as by the SOS-Chromotest.

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