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1. Aflatoxin B1 serves as an activator for protein kinase C (PKC). 2. Following activation, the enzyme translocates from the cytosol to the particulate fraction. 3. Aflatoxin B1 leads to rapid and extensive phosphorylation of the known substrate of the enzyme. 4. Aflatoxin B1 causes rapid hydrolysis of phosphatidylinositol-4,5-biphosphate to diacylglycerol and inositol-1,4,5-triphosphate.
A liquid chromatographic column-switching system containing a dialysis unit and an anti-aflatoxin immunoaffinity precolumn (immuno precolumn) is described for the automated determination of aflatoxin M1 in milk samples. Both a flat membrane dialysis unit working according to the flowing donor-flowing acceptor principle and a laboratory made hollow-fibre dialysis unit working according to the stagnant donor-flowing acceptor principle were evaluated. The hollow-fibre unit is superior with respect to repeatability (3% relative standard deviation) and detection limit (10 ng/l for aflatoxin M1 in milk), in spite of the fact that the overall recovery is only 6%. Interfering compounds, which would destroy the activity of the immuno precolumn, are efficiently removed from the system by the dialysis step; a single immuno precolumn can then be used for over 70 milk analyses. No decrease in the performance of either the immuno precolumn or the hollow-fibre dialysis unit is observed.
Several chromatographic methods for the determination of aflatoxins in agricultural and food products are reviewed. During the past two decades, identification and determination of aflatoxins were done by thin-layer chromatography (TLC) because it was easy, fast and inexpensive. However, high-performance liquid chromatography (HPLC) using fluorescence detection is now the method of choice for determining aflatoxins and is also growing in popularity for their identification. The reasons for selecting HPLC over TLC can be summarized as the ability to analyze for a wide variety of compounds, including compounds that are easily degraded by heat, light or air, the ease of adaptation to confirmatory procedures, the potential for automation and the dramatic improvement in instrumentation, including the development of increasingly sensitive fluorescence and electrochemical detectors and short, high-resolution, reversed-phase columns.
The epoxide hydrase inhibitor 1,1,1-trichloroprophane-2,3-oxide (TCPO) was genetically active to cells of S. cerevisiae and conidia of N. crassa. This genetic activity could be eliminated or reduced to near spontaneous levels in the presence of the S-9 fraction of hamster liver homogenate. The addition of TCPO to an in vitro activation system containing aflatoxin B1 resulted in an increase in the genetic activity of aflatoxin B1, and this increase was dependent on the dose of TCPO. These results are discussed in relation to the possible metabolism of the promutagen aflatoxin B1.
Aflatoxin, one of the most widespread of the known carcinogens, is present at a high level in most common foods stored poorly for long periods in Nigeria. It may work synergistically with other carcinogens to produce the high incidence of primary liver cancer seen in young men under the age of 40. In the northern savanna areas cereals, especially sorghum and millets, as well as groundnut products are the high risk foods. In the southern forest areas, dried fish, groundnuts and oil palm products often carry unwholesome quantities of aflatoxin. Public health measures aimed at reducing the aflatoxin load in high risk foods identified should now be actively considered.
Serum levels of aflatoxin B1, B2, G1 and G2 in 20 farmers (first time blood donors at Ahmadu Bello University Teaching Hospital, Zaria, Nigeria) were determined and compared with 15 patients of varied diagnoses. 25% of the farmers had levels of B1 above 0.2 microgram per ml and correspondingly the highest values of other aflatoxins. Except for the patients with nasopharyngeal carcinoma who had a B1 level of 0.13 microgram per ml, other sick control values ranged from 0.005 to 0.091 microgram per ml. None of the farmers with high levels of B1 had positive serum hepatitis B surface antigen (HbsAg) as determined by counter-immunoelectrophoresis (CIE). A continuous prospective study may define the role of aflatoxin vis-à-vis hepatitis B virus (Hbv) in the pathogenesis of the high incidence of liver disease prevalent the Guinea Savannah North of Nigeria.
The influence of water activity on the production of B1, B2, G1 and G2 aflatoxins in corn has been examined. Viable corn kernels were conditioned at three water activity levels (0.87, 0.90 and 0.97) and inoculated with Aspergillus parasiticus at 30 degrees C. Aflatoxin accumulation was determined at selected times by thin-layer chromatography. For the strain used total aflatoxin accumulation was greater at water activity 0.90 than at 0.87 and 0.97 for the incubation times studied.
A total of 100 samples of various foods comprising of 10 samples each of garri (Manihot utilis Pohl), beans (Phaseolus lunatus), yam flour (Dioscorea rotundata), cassava flour (Manihot esculentum), melon (Citrulus lunatus), onion (Allium cepa), rice (Oryza sativa), plantain (Musa paradisiaca), red pepper (Capsicum annuum L., Solanaceae) and eggs were screened for the presence of aflatoxins. Fifty percent of yam flour; 40% of cassava flour; 30% of garri; 20% of beans and melon and 10% of rice yielded aflatoxin. The implications of this incidence of aflatoxin in common foodstuff found in this community is discussed.
The growth and aflatoxin production of five Aspergillus flavus and two Aspergillus parasiticus strains isolated from natural black olives in brine for table consumption, fresh whole black olives, fresh damaged black olives and fresh black olive paste were examined. Aspergillus flavus NRRL 6555 and A. parasiticus NRRL 2999 strains were also studied for comparison. All aflatoxigenic strains inoculated onto fresh damaged black olives and fresh black olive paste grew extensively but on fresh whole black olives they grew weakly. Strong aflatoxigenic strains produced low levels of aflatoxins on fresh whole black olives, fresh damaged black olives and fresh black olive paste. Weak aflatoxigenic strains did not produce detectable amounts of aflatoxin.
The occurrence and distribution of aflatoxins B1, B2, G1 and G2 in the raw materials and products of three plants for extracting edible oils and in two poultry feedmills in which by-products of the oil extraction were used for feed formulation were investigated. While levels of aflatoxins were high in the products and by-products from the three extraction plants, the levels in the poultry feeds produced in the feedmills were found to be relatively low. The latter finding may reflect the proportion of pellets included in the feedstock formulation, while the climatic differences in the areas in which the extraction plants were situated were a possible factor in the differing levels of aflatoxin found in the samples from the three extraction plants.
The effects of chronic intra-peritoneal administration of aflatoxin B1 on the activity of alkaline and acid phosphatases; glutamic oxaloacetate (GOT) and pyruvate transaminases (GPT); 5'-nucleotidase and lactic dehydrogenase enzymes were monitored in the testis and kidney of adult albino rats. Results showed that aflatoxin B1 depressed the activity of alkaline phosphatase in both tissues, but increased that of acid phosphatase in only the testis. While GOT and 5'-nucleotidase were inhibited, GPT and lactic dehydrogenase activity was enhanced by this carcinogen. These responses were similar for the testis and kidney. The above findings coupled with the microscopical observation of the testis tissue seem to indicate that the essential lesion of this toxin on the testis may be a modification of the enzymes of germinal cells resulting from a gradual depletion of the latter. Furthermore, the results appear to show that by and large, aflatoxin B1 exerts only slightly different effects on the testis and kidney at the enzyme level.
Microsomes prepared from livers of chickens given enzyme inducers had increased capability to convert aflatoxin P1 to its glucuronide conjugate. This capability was 190% +/- 19 and 184% +/- 13 of control values (mean +/- S.E., N = 4) 96 h after intraperitoneal administration of 80 mg/kg beta-naphthoflavone or 3-methylcholanthrene, respectively. Glucuronidation of aflatoxin P1 was also increased 15 days after 500 mg/kg i.p. of a polychlorinated biphenyl mixture (to 471% +/- 111). Fifteen days on a low protein diet (containing 54% of normal levels) did not alter aflatoxin glucuronidation. Increased glucuronidation after administration of inducers was due to increased specific activity of the microsomal enzymes.
Monooxygenases of Chinese hamster livers were characterized with respect to aflatoxin B1 activation and cytochrome P450 isozymes. Polychlorinated biphenyl (PCB)-treatment induced higher activity for aflatoxin B1 activation in Chinese hamsters than in rats and this activity was more elevated by the treatment with phenobarbital than with 3-methylcholanthrene, which is contrary to the observation in Syrian hamsters and rather similar to that in rats. Western blot analysis demonstrated that the treatment of Chinese hamsters with phenobarbital markedly elevated the level of cytochrome P450 isozyme belonging to the CYP2A family and only slightly that immuno-related to CYP2B1. In parallel with this, the activities of testosterone 15 alpha-hydroxylase and 7-ethoxycoumarin O-deethylase were significantly induced by phenobarbital treatment. These suggest that phenobarbital mainly induces an isozyme related to CYP2A2 which is responsible for aflatoxin B1 activation in Chinese hamsters.
Hamster liver microsome-mediated [14C]aflatoxin B1 binding to DNA is inhibited by 105,000 X g liver supernatant fraction. Absolute requirement of glutathione for the inhibitory activity of the dialyzed supernatant and irreversible loss of the inhibitory activity by the heat-treated supernatant indicate involvement of glutathione S-transferase. Concomitant with inhibition of aflatoxin B1-DNA binding, the formation of an aflatoxin B1-glutathione conjugate is indicated.
The effect of aflatoxin B1 on the binding capacity of rat liver cytoplasmic glucocorticoid receptors and the nuclear binding of the activated receptor complex was investigated. No alterations in the kinetics of [3H]desamethasone-cytosol receptor complex formation were noted 2 h after treatment with 1 mg/kg aflatoxin B1. However, a 33% decrease in the concentration of nuclear acceptor sites and a 24% decrease in the glucocorticoid receptor-nuclear binding equilibrium constant of dissociation was observed. This response was near maximal at 2 h and persisted for at least 26 h. Inhibition of nuclear binding capacity was directly related to aflatoxin B1 dose, with a correlation coefficient of 0.99. Actinomycin D treatment (0.1 mg/kg) resulted in a slight reduction (16%) in the concentration of nuclear acceptor sites but had no effect on the nuclear binding dissociation constant. Administration of [3H]dexamethasone to alfatoxin B1 -treated rats produced a similar pattern of glucocorticoid binding distribution in vivo to that observed in vitro. No differences in [3H]dexamethasone-cytoplasmic receptor binding between control and alfatoxin B1 -treated rats were found, whereas nuclear [3H]dexanthasone binding was reduced 34% by alfatoxin B1 -treatment.
A cDNA encoding a novel member of the cytochrome P-450 superfamily, Cyp3a-13, has been isolated from mouse liver cDNA library by hybridization screening. The Cyp3a-13 encoded 503 amino acid residues and shared 71% amino acid identity with Cyp3a-11. When Cyp3a-13 cDNA was expressed in CR119 cells which had been established as a cell line stably expressing NADPH-cytochrome P-450 reductase cDNA of guinea pigs, aflatoxin B1-dependent cytotoxicity was observed. This cytotoxicity was enhanced by alpha-naphthoflavone (7,8-benzoflavone), which is known to augment the CYP3A enzymatic activity. The results indicate that CYP3A in mice, which are relatively insensitive to aflatoxin B1, can activate aflatoxin B1 to a genotoxic product.
An investigation of the effects of aflatoxin B1 on rat testes and plasma estrogens is reported. A normal saline-suspended aflatoxin B1 was injected into right testes of mature Sprague-Dawley rats at doses of 0, 5, 10, 25 or 50 micrograms. Effects were evaluated by histopathological alterations of the testes and by levels of plasma estrogens estimated by a modified Dextron-Charcoal radioimmune assay. Significant gross lesions were present in testes injected with the 50 microgram dose. There was a 50% reduction in size and weight as compared to the left testis. Histological changes were dose-dependent, with minimal or no changes at 5 micrograms and maximal effects at 50 micrograms. The lesions varied from mild testicular degeneration to complete disappearance of cellular components. Interstitial cell proliferation, occasional calcification of seminiferous tubules, and absence of spermatogenesis and spermatozoa were extreme toxic effects. Estrogen concentrations in injected rats were reduced compared to those of control and normal rats. This study suggested that following intratesticular aflatoxin B1 exerts a direct toxic effect on testes with a reduction in plasma estrogen levels.
The embryotoxicity of aflatoxins B1, B2, G1, G2 and M1 was investigated after administration to chick embryos on either Day 2, 3 or 4. Treatment resulted mainly in embryolethality and a rank order for embryotoxicity was established where B1 greater than G1 greater than M1 = B2 greater than G2. The sensitivity of embryos to aflatoxin administration decreased with their age. These results document the general cytotoxic character of aflatoxin action upon the embryonic morphogenetic systems, actions that apparently require neither specific metabolic activation nor any specific target.