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PubMed1997

[In vitro adsorption of aflatoxins by means of sorbent compounds: montmorillonite].

Aflatoxins are a group of mycotoxins that can be present as contaminants in a great number of food and feedstuffs. It has been demonstrated that non-nutritive adsorbent compounds are able not only to adsorb aflatoxins but also to prevent its gastrointestinal absorption. The objective of this study is to evaluate the adsorptive capacity of a montmorillonite (a natural silicate) with regard to aflatoxins, and to evaluate the efficacy and stability of the aflatoxin-montmorillonite complex in several pH, temperature and reaction media. Results have demonstrated that, at a concentration of 1% w/v, this adsorbent has a high efficacy in the sorption of aflatoxins, with mean sorption percentages higher than 98% in most of cases. Physisorption is probably the sorption mechanism of this process.

English Abstract↗

PubMed1987

Temperature and aflatoxin production by Aspergillus flavus and A. parasiticus strains from Nigerian groundnuts.

The ability of four strains of Aspergillus parasiticus (IMI 301,001) and two strains of Aspergillus flavus (IMI 300,998) to produce aflatoxins on Nigerian groundnuts under varying conditions of temperature was studied. While all the A. parasiticus strains produced the four major aflatoxins (B1, B2, G1, G2), only aflatoxin B1, and B2 were produced by the A. flavus strains used. The optimum temperature for aflatoxin production by both the fungal species was 30 degrees C with no toxin production at 10 degrees C.

Aflatoxin B1↗

PubMed1996

The kinetics of aflatoxin B1 oxidation by human cDNA-expressed and human liver microsomal cytochromes P450 1A2 and 3A4.

The combined presence of CYP1A2 and 3A4, both of which oxidize aflatoxin B1 (AFB1) to the reactive aflatoxin B1-8,9-epoxide (AFBO) and to hydroxylated inactivation products aflatoxin M1 (AFM1) and aflatoxin Q1 (AFQ1), substantially complicates the kinetic analysis of AFB1 oxidation in human liver microsomes. In the present study, we examine the reaction kinetics of AFB1 oxidation in human liver microsomes (HLMs, N = 3) and in human CYP3A4 and CYP1A2 cDNA-expressed lymphoblastoid microsomes for the purpose of identifying the CYP isoform(s) responsible for AFB1 oxidation at low substrate concentrations approaching those potentially encountered in the diet. AFBO formation by cDNA-expressed human CYP1A2 followed Michaelis-Menten kinetics (Km = 41 microM, Vmax = 2.63 nmol/min/nmol P450). Furthermore, the portion of AFBO formed in HLMs which was eliminated by furafylline, a specific mechanism-based inhibitor of CYP1A2, also followed Michaelis-Menten kinetics (Km = 32-47 microM, Vmax = 0.36-0.69 nmol/min/nmol P450). The formation of AFBO (activation product) and AFQ1 (detoxification product) in cDNA-expressed human CYP3A4 microsomes was sigmoidal and consistent with the kinetics of substrate activation. Accordingly, application of a sigmoid Vmax model equivalent to the Hill equation produced excellent fits to the cDNA-expressed CYP3A4 data and also to the data from HLMs pretreated with furafylline to remove CYP1A2. The Hill model predicted that two substrate binding sites are involved in CYP3A4-mediated AFB1 catalysis and that the average affinity of AFB1 for the two sites was 140-180 microM. Vmax values for AFQ1 formation were 10-fold greater than those for AFBO, and total substrate turnover to both was 67 nmol/min/nmol CYP3A4. Using the derived kinetic parameters for CYP1A2 and 3A4 to model the in vitro rates of AFB activation at low substrate concentrations, it was predicted that CYP1A2 contributes to over 95% of AFB activation in human liver microsomes at 0.1 microM AFB. The important role of CYP1A2 in the in vitro activation of AFB at low substrate concentrations was supported by DNA binding studies. AFB1-DNA binding in control HLMs (reflecting the contribution of CYP1A2 and CYP3A4) and furafylline-pretreated microsomes (reflecting the contribution of CYP3A4 only) catalyzed the binding of 1.71 and 0.085 pmol equivalents of AFB1 to DNA, respectively, indicating that CYP1A2 was responsible for 95% of AFB1-DNA adduct formation at 0.133 microM AFB. These results demonstrate that CYP1A2 dominates the activation of AFB in human liver microsomes in vitro at submicromolar concentrations and support the hypothesis that CYP1A2 is the predominant enzyme responsible for AFBO activation in human liver in vivo at the relatively low dietary concentrations encountered in the human diet, even in high AFB exposure regions of the world. However, because the actual concentrations of AFB in liver in vivo following dietary exposures are uncertain, additional studies in exposed human populations are needed. Quantitative data on the relative rates of AFM1 and AFQ1 excretion (potential biomarkers for CYP1A2 and 3A4 activity, respectively) in humans would be useful to validate the actual contributions of these two enzymes to AFB1 oxidation in vivo.

Adult↗

PubMed1989

Mutagenesis by aflatoxin in M13 DNA: base-substitution mechanisms and the origin of strand bias.

The two goals of the experiments described here are: (a) to examine whether there is a strand bias in mutagenic processing of bulky lesions in M13 replicative form (RF) DNA, and (b) to examine the mutational mechanisms of metabolically activated aflatoxin. For these experiments, two types of nicked heteroduplex M13 RF DNA molecules (+WT/-am1 and +am1/-WT) in which either the minus (-) or the plus (+) strand carried a gene 1 amber nonsense codon, were constructed. Heteroduplex DNAs were modified in vitro with aflatoxin B1 activated by hamster liver S9 enzymes, and transfected into SOS(UV)-induced Escherichia coli (Supo/uvrA-/mucAB+). Forward mutations in the lacZ alpha-complementing gene segment were scored and sequenced. Results indicated that aflatoxin-induced mutation frequencies in the +WT/-am1 heteroduplex were significantly greater than those in the +am1/-WT heteroduplex, suggesting more efficient mutagenic processing of lesions in the plus strand. These results permit specific suggestions for improved mutation detection in the extensively used M13 forward mutagenesis system. Sequence analysis of point mutations from the +WT/-am1 experiments showed that most substitutions were targeted to plus-strand guanines. Both G-to-A transitions and G-to-T transversions were induced with equal efficiency. Since activated aflatoxin B1 is known to react almost exclusively with DNA guanines at the N7 position, these results suggest that bulky lesions at guanine N7 position may have the properties of mis-instructional as well as non-instructional lesions.

Aflatoxin B1↗

PubMed1991

Occurrence of aflatoxins in parboiled rice in Sri Lanka.

In Sri Lanka, rice is the main staple which is mostly processed into parboiled rice. The levels of aflatoxin B1 (AFB1) and aflatoxin G1 (AFG1) in parboiled and raw milled rice collected from major rice producing areas and rice consuming townships were estimated. In almost all the samples of parboiled rice examined, the AFB1 and AFG1 contents were significantly higher than in raw milled rice. The highest AFB1 content was 185 micrograms/kg and AFG1 content 963 micrograms/kg. These samples were collected from a major rice producing/milling district where the mean relative humidity is 78% and mean annual temperature 27 degrees C which is the highest amongst the rice growing areas in Sri Lanka. Raw rice was either free of aflatoxins or when toxins were detected, they occurred in less than 10% of the samples. The frequency of occurrence of surface fungal flora (Aspergillus/Penicillium) and aflatoxin content in market samples was closely related. Brownish or greenish moldly rice samples with fermented odour contained over 1000 micrograms/kg of AFB1.

Aflatoxin B1↗

PubMed1987

Aflatoxin B1 production in orange (Citrus reticulata) juice by isolates of Aspergillus flavus Link.

Out of 7 isolates of Aspergillus flavus obtained from rotting orange (Citrus reticulata) fruits, 3 isolates were found to be toxigenic, producing variable amounts of aflatoxin B1 on a semisynthetic liquid medium. The most toxigenic isolates were further evaluated in plain juice and juice supplemented either with 0.05% yeast extract or 0.5% sucrose or both, at three different incubation periods. The maximum yield of aflatoxin B1 (162.5 micrograms/25 ml) was obtained from the juice supplemented with both sucrose and yeast extract within an incubation period of 10 days, whereas a sharp decline in aflatoxin B1 (30 micrograms/25 ml) was observed when incubation was extended beyond 10 days. The addition of yeast extract has a promoting effect on the yield of aflatoxin in comparison to the sucrose.

Aflatoxin B1↗

PubMed1990

Intercellular variation in levels of adducts of aflatoxin B1 and G1 in DNA from rat tissues: a quantitative immunocytochemical study.

Adducts between aflatoxin B1 and G1 and DNA have been visualised and quantified in various rat tissues by a sensitive immunocytochemical approach. The quantitative validity of this assay has been examined by comparison with experiments using radioactively labelled aflatoxin. Rats were exposed to single and multiple doses of aflatoxin and a marked intercellular variation in adduct levels was observed in kidney and lung, in contrast to the liver, where binding was more homogeneous. No adducts were detected in the oesophagus, forestomach, colon, spleen or testes (detection limit approximately 300 pg aflatoxin/mg DNA). The DNA adduct data are discussed in relation to the carcinogenicity of aflatoxin B1 and G1.

Aflatoxin B1↗

PubMed1981

Determining the kinetic behaviour for the secretion of milk toxin as related to dosage level of aflatoxin B1.

39 species which belong to 14 genera were isolated from 110 milk samples collected from different dairy sources at Assiut City. The most frequent fungi were A. niger, A flavus and Clasdosporium cladosporioides, followed by Curvularia spicifera and Penicillium corylophilum. The remaining species were of rare occurrence. The fluorescence-method for detecting aflatoxin-producing strains demonstrated the presence of two isolates namely A. flavus possesses this property. One of these toxic isolates was proved to produce high level of aflatoxin B1. It was used as a tool for determining the kinetic behaviour for the secretion of M1 toxin in milk of lactating animals which had received a toxic diet. The results revealed the following: 1. The milk toxin was detected in the milk of lactating animals next day after the toxin-containing ration was fed. 2. The level of milk toxin is gradually decreased when the feeding programme was interrupted. 3. When the animals supplied a ration containing the same concentration of aflatoxin for successive days, the milk toxin concentration was maintained at the same level. 4. The total amount of milk toxin secreted was less than one per cent of the amount of aflatoxin B1 received. 5. The concentration of milk toxin secreted by goats was higher than that of dairy cows. 6. Milk toxin failed to be detected five days after the feeding programme was discontinued.

Aflatoxin B1↗

PubMed1988

Effect of nutritional factors on aflatoxin B1 inhibition of growth in Escherichia coli and Salmonella typhi.

The extent of growth inhibition by aflatoxin B1 in S. typhi and E. coli was greater in the presence of sodium citrate or sodium phosphate, palmitic and stearic acid than aflatoxin B1 alone. The addition of amino acids (glycine or glutamic acid) stimulated growth in E. coli and inhibited in S. typhi in the presence of aflatoxin B1. Other nutrients, such as yeast extract, lactose, or salt addition did not alter aflatoxin B1 antibacterial activity but decreased growth was observed in the presence of peptone.

Aflatoxin B1↗

PubMed1983

Metabolic basis of the species difference to aflatoxin B1 induced hepatotoxicity.

Primary metabolism of aflatoxin B1 by the liver microsomal enzymes from a range of animal species showed both quantitative and qualitative differences. Quail was shown to have the most rapid metabolism of aflatoxin B1. The major product of metabolism in this case was found to be aflatoxin B1-8,9-dihydrodiol suggesting that the quail microsomes produced high levels of the proposed reactive intermediate aflatoxin B1-8,9-epoxide. Using this system to generate the epoxide, the ability of the cytosol prepared from each species to conjugate epoxide with reduced glutathione was investigated. Large differences in ability to conjugate were observed ranging from 0 to 72% for quail and mouse respectively. Differences in both primary and secondary metabolism of AFB1 were noted between male and female Fischer 344 rats.

Aflatoxin B1↗

PubMed1990

Aflatoxin B1-specific cytochrome P-450 isozyme (P-450-AFB) inducible by 3-methylcholanthrene in golden hamsters.

Hepatic microsomes of polychlorinated biphenyl (PCB)-treated Syrian Golden hamsters possessed a higher potency toward aflatoxin B1 activation, based on the Ames test, than other animal species. This activity was induced in hamsters preferentially by treatment with 3-methylcholanthrene rather than phenobarbital. The contribution of an isozyme of cytochrome P-450 (P-450-AFB) to the activity of hamster livers for aflatoxin B1 was studied. P-450-AFB, purified from 3-methylcholanthrene-treated hamster livers, was shown to possess the highest activation of aflatoxin B1 in the Ames test. The quantification of this isozyme by a fluorometric sandwich enzyme-linked immunosorbent assay (ELISA) demonstrated that P-450-AFB was induced mainly in Syrian Golden hamsters but not in Chinese hamsters, or in other species. This isozyme constitutes approximately 40% of the total cytochrome P-450 of the hepatic microsomes from 3-methylcholanthrene-treated Golden hamsters but only 1% in the microsomes of phenobarbital-treated hamsters. Thus, we conclude that the high activity of Golden hamster livers towards aflatoxin B1 activation was due presumably to this distinct and unique cytochrome P-450 isozyme which was induced mainly by 3-methylcholanthrene in Golden hamsters.

Aflatoxin B1↗

PubMed1990

Effect of ethanol on hepatotoxicity and hepatic DNA-binding of aflatoxin B1 in rats.

The hepatocarcinogen aflatoxin B1 is converted to reactive metabolites that bind covalently to cellular macromolecules. These metabolites may also react with glutathione, resulting in the formation of glutathione conjugates and detoxication of the reactive metabolite. When rats were pretreated with ethanol by gastric intubation at a dose of 100 mmol/kg, 6 hr (the time of maximal GSH depletion) before the administration of aflatoxin B1, the covalent binding of 8,9-epoxide-aflatoxin B1 to DNA in vivo was increased by 47% and the hepatotoxicity was also potentiated. However, the covalent binding was not increased by pretreatment with ethanol 18 hr (time with approximately normal GSH levels) before administration of the toxin, and no potentiation of hepatotoxicity was observed. Pretreatment with a non-toxic dose of ethanol had no effects on the activity of glutathione S-transferase and glutathione peroxidase. These results suggest that the depletion of GSH and the increased formation of DNA-adduct from the liver constitute an important mechanism for the potentiation of aflatoxin B1-induced hepatotoxicity by ethanol.

Aflatoxin B1↗

PubMed1981

Activation of aflatoxin B1 by primary cultures of adult rat hepatocytes: effects of hepatocyte density.

Primary monolayer cultures of adult rat hepatocytes readily activate aflatoxin B1 as determined by bacterial mutagenesis (Ames test) and the extent of apparent covalent binding of aflatoxin B1 residues to hepatocyte macromolecules. For intact cultures inoculated with 3 X 10(5)-3 X 10(6) cells/dish, the efficiency of activation decreases with increasing cell density whereas permeabilized hepatocytes prepared from similarly-handled monolayer cultures show with increasing protein proportional increases in the capacity to activate aflatoxin B1. The density effect observed with intact cultured hepatocytes appears not to be due to substrate (aflatoxin B1) or oxygen depletion. These findings have apparent relevance to studies of carcinogen metabolism and in the design of carcinogen/mutagen testing protocols which utilize cultured hepatocytes.

Aflatoxin B1↗

PubMed1989

Aflatoxin B1 formamidopyrimidine adducts in human hepatocarcinogenesis: a preliminary report.

The presence of aflatoxin-B1-formamidopyrimidine, a persistent aflatoxin-deoxyribonucleic acid (DNA) adduct, was investigated in vivo by immunohistochemical analysis in 14 paired hepatocellular carcinoma and nontumorous human liver tissue sections using a monoclonal anti-aflatoxin-B1-formamidopyrimidine antibody. Nuclear and cytoplasmic accumulations of adducts were found in 4 of 14 nontumorous specimens but in none of 14 tumorous tissues and in none of three normal control livers. In vitro adduct formation and cellular DNA was investigated with a modified DNA immunoblot assay. These studies revealed (a) no significant difference in the amount of adduct formed by DNA samples with or without integrated hepatitis B virus DNA, (b) no difference in the amount of adduct formed with DNA from either tumorous or nontumorous tissues from a given individual, and (c) remarkable and reproducible differences in the capacity of DNA from different individuals to form in vitro adducts. Our DNA immunoblot assay will facilitate further studies on the molecular role of aflatoxin-B1-form-amidopyrimidine adducts in human hepatocarcinogenesis.

Aflatoxin B1↗

PubMed1981

Metabolic activation of aflatoxin B1 by liver tissue from male fischer F344 rats of various ages.

The effect of aging on the ability of the liver to activate chemical procarcinogens was studied using 12-, 18-, and 27-month-old male Fischer F344 rats. The cytochrome P-450 content of the S9 and microsomal fractions of the liver decreased approximately 30% between 12 and 18 months of age. The structural conformation of cytochrome P-450 in microsomes from 12-, 18-, and 27-month-old rats was studied using electron-spin resonance spectroscopy. An age-related decrease in the amount of cytochrome P-450 ferric iron in the liver microsomes was observed. The conversion of the chemical procarcinogen aflatoxin B1 to mutagenic compounds by the S9 and microsomal fractions of liver was measured using the Salmonella typhimurium bioassay. A 40-50% decrease in the metabolic activation of aflatoxin B1 was observed between 12 and 18 months of age. However, the activation of aflatoxin B1 did not change after 18 months of age. The age-related decrease in the activation of aflatoxin B1 by liver appears to be due to a decrease in the metabolic activity of the mixed-function oxidase system.

Aflatoxin B1↗

PubMed1989

Prophage induction by 4 antimalaria drugs (daraprim, fansidar, nivaquine and camoquine) and in combination with aflatoxin B1.

The abilities of 4 antimalaria drugs (Daraprim, Fansidar, Nivaquine and Camoquine) on their own and in combination with aflatoxin B1 to induce prophage in tester strains E. coli D21 and D22 were studied. The 4 drugs were found to induce prophage in the tester strains; Daraprim and Fansidar without the need for activation by liver mixed function oxidases (S9 microsomal fraction), while Nivaquine and Camoquine did require activation by this system. Aflatoxin B1 was used as a positive control in all the tests. The combined effects of each of the drugs with aflatoxin B1 were lower than that of the individual drugs acting alone. From these results, it may be concluded that the drugs may, on their own, pose a carcinogenic hazard to the population in the Nigerian environment exposed to them. In addition, the depression of prophage induction observed when the drugs were combined with aflatoxin B1 may be indicative of a common target site of action in the tester strains.

Aflatoxin B1↗

PubMed1983

Changes in preneoplastic response to aflatoxin B1 in rats fed green beans, beets or squash.

Weanling male Fischer rats were fed diets containing 25% freeze-dried green beans, beets or squash either with or without 1 ppm aflatoxin B1 for 8 wk. Plasma alpha-foetoprotein concentrations were determined weekly from wk 4 to 7. During wk 8 the animals were killed and hepatic sections were stained for gamma-glutamyl transpeptidase. All three vegetable diets, as compared to the basal semi-purified diet, enhanced both aflatoxin-B1-induced elevation of plasma alpha-foetoprotein and aflatoxin-B1-induced emergence of hepatic cell foci of gamma-glutamyl transpeptidase. The data suggest that these vegetables contain natural factors that enhance aflatoxin B1 carcinogenicity.

Aflatoxin B1↗

PubMed1988

Enhanced ethanol-induced changes in disposition and toxic response to dietary aflatoxin B1 due to Sacoglottis gabonensis bark extract, a Nigerian alcoholic beverage additive.

The disposition of, and toxic response, to, dietary aflatoxin B1 (AFB1) was investigated in rats ingesting small doses of Sacoglottis gabonensis bark extract, ethanol, or both, in the drinking-water. Ingestion of ethanol alone or with the bark extract for 8 days resulted in a significant reduction in the level of AFB1 bound to serum albumin, but the level of unbound aflatoxin in the serum was significantly depressed only by concurrent ingestion of ethanol and the bark extract. In contrast, the bark extract alone or with ethanol significantly enhanced AFB1 binding to hepatic DNA. As with serum aflatoxin, concurrent ingestion of ethanol and the extract caused the most pronounced effect, suggesting synergism. All three treatments interfered with both the daily excretion pattern, and level, of aflatoxin in the urine. All three treatments enhanced AFB1-induction of liver gamma-glutamyltranspeptidase activity, suggesting potentiation of toxic response to AFB1. These data suggest that addition of the bark extract to alcoholic beverages may affect the biological response to dietary AFB1.

Aflatoxin B1↗