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PubMed1990

Interaction between aflatoxin B1 and oxytetracycline in isolated rat hepatocytes.

Isolated rat hepatocytes were used as an in vitro model to investigate a possible interaction between oxytetracycline (OXT) and aflatoxin B1 (AFB1). LDH leakage, RNA and protein synthesis and glycogen accumulation were measured in the presence of both drugs, either separately or in combination. The evolution of LDH leakage during the incubation was identical in untreated and treated cells. AFB1 inhibited RNA and protein synthesis at a concentration of 10(-7) M and 10(-6) M, respectively, and higher, whereas OXT did not influence RNA synthesis but inhibited protein synthesis at the highest tested concentration, 10(-3) M. As far as glycogen is concerned, rats were injected with glucagon before sacrifice in order to obtain a constant synthesis rate in isolated hepatocytes. AFB1 inhibited the accumulation of glycogen from 10(-6) M upward. This effect was never observed before 90 min of incubation. OXT had no effect on glycogen synthesis. In the presence of both drugs, no interaction was demonstrated as far as RNA and protein synthesis were concerned, but OXT opposed the inhibition induced by AFB1 on glycogen accumulation. If the "in vivo" protection, provided by OXT against AFB1-induced toxicity, is due to a direct interference in the toxic mechanisms of the mycotoxin, these results show that OXT does not influence the AFB1-inhibition of RNA and protein synthesis. The latter are early and sensitive parameters inhibited by AFB1. On the contrary, taking into consideration the results on glycogen accumulation, it seems more interesting to investigate further this metabolism.

Aflatoxin B1↗
PubMedDate not supplied

Qualitative method for determination of aflatoxin B1 in nuts.

The proper characterization of a commercial qualitative method for determining aflatoxin B1 in some nuts is described. A qualitative method that provides binary responses of the yes/no type means that the performance parameters have been properly adapted and defined. Performance characteristics such as the cut-off limit, the detection limit, sensitivity, specificity, false-positive and negative rates, and the unreliability or uncertainty region are defined and then estimated by means of the performance characteristic curves. The commercial test kit showed the cut-off limit at 1.6 ng/g, with a sensitivity rate of 95% and a false-negative rate of zero. A modification can be performed to shift the cut-off to 2.0 ng/g, keeping the same values for the sensitivity and false-negative rate.

Aflatoxin B1↗
PubMed1991

An examination of the effect of pretreatment of rats with Sacoglottis gabonensis bark extract, a Nigerian palmwine additive, and ethanol on macromolecular binding of aflatoxin B1.

In a previous study (Okoye and Neal, Food and Chemical Toxicology 1988, 26, 679) enhanced ethanol-induced reductions in albumin-bound and unbound serum aflatoxin B1 (AFB1) and increased hepatic DNA-AFB1 binding were observed in rats treated with bark extract of Sacoglottis gabonensis, a Nigerian palmwine additive. The present study was designed to examine further the mechanism of these effects. Male weanling rats were pretreated with the bark extract or ethanol, or both, in drinking-water (at three times the levels used in the previous study) for 8 days before the ip administration of a single dose of [3H]AFB1. [In the previous study the rats were fed all three compounds simultaneously.] In contrast to the results of the previous study, when both the additive and ethanol were administered, there were no significant effects on [3H]AFB1 binding to liver or serum albumin or liver DNA. The levels of DNA-bound aflatoxin were reduced in rats given the additive or ethanol alone.

Aflatoxin B1↗
PubMed2001

Determination of aflatoxins B1, B2, G1 and G2 in spices using a multifunctional column clean-up.

A rapid and simple method using a multifunctional column, which contains lipophilic and charged active sites, was developed to analyse aflatoxins B1, B2, G1 and G2 in various spices, such as red pepper and nutmeg. After extraction by acetonitrile:water (9:1) and clean-up using MultiSep #228 column, the aflatoxins and aflatoxin-TFA derivatives are determined using LC with fluorescence detection. Recoveries of each aflatoxin B1, B2, G1 and G2 spiked to red pepper, white pepper, black pepper, nutmeg and tear grass at the level of 10 ng/g were over 80-85% in all instances. The minimum detectable concentration for aflatoxins in red pepper was 0.5 ng/g.

Aflatoxins↗
PubMed1980

Activation of aflatoxin B1 by a mono-oxygenase system localized in rat liver mitochondria.

Structurally intact rat liver mitoplasts free of detectable microsomal contamination contain enzymatic activity to metabolize aflatoxin B1 (AFB1). The activated component(s) bind to mitochondrial macromolecules and also inhibit mitochondrial protein synthesis. The activity of intact mitoplasts or sonicated particles is partly dependent on the addition of NADPH-generating system. Under optimal conditions, the mitochondrial enzyme has specific activity of 60 to 65 pmol/mg and represents about 15 to 18% of total cytoplasmic activity for AFB1 activation. The enzyme is localized in the soluble fraction of mitochondrial matrix and appears to be distinctly different from the microsomal activity.

Aflatoxin B1↗
PubMed1986

New species of messenger RNA in aflatoxin B1 induced hepatocellular carcinoma.

Differences in the mRNA species were observed when cDNA complementary to HnRNA from normal liver was hybridized with mRNA from hepatocellular carcinoma induced by aflatoxin B1. The hybridizations between cDNA complementary to HnRNA from liver cell carcinoma and HnRNA from normal liver indicate that there is homology between their sequences. The findings in this paper suggest that mRNA species normally restricted to the cell nucleus are present in the cytoplasm of liver carcinoma cells.

Aflatoxin B1↗
PubMed1986

Is the activation of aflatoxin B1 catalysed by the same form of cytochrome P-450 as that 4-hydroxylating debrisoquine in rat and/or man?

A possible association between the metabolic activation of aflatoxin B1 (AFB1) to a mutagen and the 4-hydroxylation of debrisoquine, which shows genetic variation both in man and in the rat, was investigated. Hepatic microsomal fractions from female DA and Fischer rats catalyse, at the same rate, the conversion of AFB1 to a mutagenic and arylating metabolite, that bound covalently to microsomal proteins. Debrisoquine was without effect on either of these reactions. In contrast, metyrapone did inhibit the mutagenic activation of AFB1. Microsomal fraction from human liver was also capable of activating AFB1 to a mutagenic and arylating metabolite. Again, debrisoquine was without appreciable effect on these reactions. In contrast, cimetidine caused profound inhibition of the mutagenic activation of AFB1. It is concluded that the activation of AFB1 to a mutagenic, and presumably carcinogenic, metabolite is catalysed by a different form of cytochrome P-450 from that catalysing the 4-hydroxylation of debrisoquine, both in rat and in man.

Aflatoxin B1↗
PubMed2005

Breast cancer resistance protein (Bcrp1/Abcg2) reduces systemic exposure of the dietary carcinogens aflatoxin B1, IQ and Trp-P-1 but also mediates their secretion into breast milk.

The breast cancer resistance protein (BCRP/ABCG2) usually protects the body from a wide variety of environmental and dietary xenotoxins by reducing their net uptake from intestine and by increasing their hepatobiliary, intestinal and renal elimination. BCRP is also highly expressed in lactating mammary glands in mice, and this expression is conserved in cows and humans. As a result, BCRP substrates can be secreted into milk. We investigated whether different classes of dietary carcinogens are substrates of Bcrp1/BCRP and the implications for systemic exposure and breast milk contamination. Using polarized cell lines, we found that Bcrp1 transports the heterocyclic amines 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and the potent human hepatocarcinogen aflatoxin B1, and decreases their cellular accumulation up to 10-fold. In vivo pharmacokinetic studies showed that [14C]IQ, [14C]Trp-P-1 and [3H]aflatoxin B1 plasma levels were substantially lower in wild-type compared with Bcrp1-/- mice, after both oral and intravenous administration, demonstrating that Bcrp1 restricts systemic exposure to these carcinogens. Moreover, Bcrp1 mediates transfer of [14C]IQ, [14C]Trp-P-1 and [3H]aflatoxin into milk, with 3.4+/-0.6, 2.6+/-0.3 and 3.8+/-0.5-fold higher milk to plasma ratios, respectively, in lactating wild-type versus Bcrp1-/- mice. We have thus identified Bcrp1/BCRP as one of the molecular mechanisms by which heterocyclic amines and aflatoxin are transferred into milk, thereby posing a health risk to breast-fed infants and dairy consumers. Paradoxically, Bcrp1/BCRP appears to have both protective and adverse roles with respect to exposure to dietary carcinogens.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMed1985

Comparative cytopathology of primary rat hepatocyte cultures exposed to aflatoxin B1, acetaminophen, and other hepatotoxins.

The cytomorphological alterations in primary monolayer cultures of Fischer 344 rat hepatocytes exposed continuously to lethal concentrations of various hepatotoxins were compared. Aflatoxin B1 (AFB1) at concentrations of 1 and 10 microM killed 67 and 97% hepatocytes, respectively, at 48 hr, as determined by release of lactate dehydrogenase (LDH) into culture medium, or by trypan blue uptake. AFB1 produced numerous radial finger-like projections (blebs) at attached margins of cytoplasm in almost all hepatocytes between 6 and 24 hr. Formation of blebs was dose dependent and preceded release of LDH and trypan blue uptake. Similar marginal blebs were produced by cycloheximide, 2-acetylaminofluorene, N-hydroxy-2-acetylaminofluorene, and senecionine. By comparison, acetaminophen, at equivalently lethal concentrations (4 or 16 mM) did not cause marginal blebs, but resulted in a similar time course of LDH release and trypan blue uptake. Carbon tetrachloride and bromobenzene also failed to produce blebs at lethal concentrations. Phalloidin and cytochalasin B rapidly produced smaller spherical blebs over the entire surface of all hepatocytes, distinct from the finger-like blebs produced only at the free attached margins of cells exposed to AFB1. Blebs and lethal injury by AFB1 were reduced by phenobarbitone or 3-methylcholanthrene pretreatments and by SKF-525-A in culture. The demonstration of morphological prelethal changes in hepatocytes injured by different classes of hepatotoxins in culture provides a means of differentiating the early biochemical mechanisms by which hepatotoxins and hepatocarcinogens lethally injure hepatocytes before membrane permeability to LDH and trypan blue is detectable.

Acetaminophen↗
PubMed1998

Occurrence of aflatoxins B1, B2, G1, and G2 in peanuts and their products marketed in the region of Campinas, Brazil in 1995 and 1996.

Samples of peanuts and their products marketed in the region of Campinas, Brazil in 1995 and 1996 were analysed in terms of aflatoxin B1, B2, G1, and G2 by thin-layer chromatography, aiming at the protection of consumer health. Of the 80 samples analysed, 35 of peanuts and 45 of peanut products, 41 (51%) presented contamination with aflatoxin, 11 of them being peanuts (27%) and 30 being products (67%), in a range of 43 to 1099 micrograms/kg for B1 + B2 + G1 + G2 with a 90th percentile of 415 (B1 + G1) and of 615 (B1 + B2 + G1 + G2). The results also demonstrated that aflatoxin B1 (AFB1) reached the highest incidence and the highest upper limits compared with all the other aflatoxins.

Aflatoxin B1↗
PubMed1986

Dose-related inhibition of aflatoxin B1 induced hepatocarcinogenesis by the phenolic antioxidants, butylated hydroxyanisole and butylated hydroxytoluene.

The effect of butylated hydroxyanisole (BHA) or butylated hydroxytoluene (BHT) on the carcinogenicity in rats of aflatoxin B1 (AFB1) was investigated. AFB1 was administered by gastric intubation to male F344 rats at 25 micrograms/kg body wt three times a week such that a total dose of 1.5 mg/kg (0.48 mmol/kg) body wt was given over a period of 20 weeks and diets containing either 1000 or 6000 p.p.m. BHA or BHT were fed starting one more week before carcinogen, during administration and for one week after cessation. Animals were killed during exposure and at intervals up to 24 weeks after cessation. Liver altered foci and neoplasms were quantified using the exclusion of cellular iron after iron-loading and gamma-glutamyl transpeptidase reaction, as well as conventional staining for identification. Exposure to AFB1 alone induced substantial numbers of altered foci after 20 weeks, and at 24 weeks after cessation of exposure, the incidence of hepatocellular neoplasms was 63%. In the groups receiving BHA or BHT together with AFB1, the numbers of altered foci were decreased at all time points and at termination, the final incidence of liver cell neoplasms and number of neoplasms per animal were also reduced in a dose-related manner. Neoplasms in other organs were rare and were not affected by antioxidant treatment, except for a possible reduction of colon cancer. Thus, BHA and BHT inhibited the hepatocarcinogenesis of concurrently administered AFB1 without shifting the organotropism.

Aflatoxin B1↗
PubMed1986

Modulation by certain factors of metabolic activation of aflatoxin B1 as detected in vitro in a simple fluorimetric assay.

Forty compounds belonging to various chemical groups have been tested for their ability to suppress metabolic activation of aflatoxin B1 (AFB1) mediated by rat liver microsome. Microsomal activation has been carried out in an in vitro system containing Tris-buffer at pH 7.2. Production of the reactive metabolite, AFB1 8,9-epoxide, has been measured by separation and detection of its hydrolysis product AFB1 8,9-dihydrodiol as the Tris-diol complex. The complex is separated using simple procedures of biphasic extraction and deproteinization, and detected by its characteristic fluorescence. Quantitation is made by direct comparison of its fluorescence with that of an authentic Tris-diol prepared synthetically. The method is rapid and proved to be highly sensitive and reproducible. A large number of compounds have been observed to modulate at varying degrees the activation of AFB1 in this in vitro system. Many compounds have been tested at several concentration ranges and inhibition curve is constructed in each case from which ID50 values, i.e., the dose needed to bring about 50% inhibition can be obtained. These values expressed as nmol afford a direct and realistic comparison of the inhibitory potential of various modulators. Factors having great inhibitory potential have been identified as retinoids (retinol, retinal, retinoic acid, retinyl acetate), beta-carotene, riboflavin, ascorbic acid, copper, zinc, linoleic acid, p-hydroxy benzoic acid, butylated hydroxyanisole, butylated hydroxytoluene, disulfiram, and phenothiazine. Several other compounds have shown moderate inhibitory potential. The strong inhibition on Tris-diol formation by several vitamins, antioxidants and trace metals shows similarity with their effect on AFB1-DNA adduct formation. It is suggested that these agents may have potential anticarcinogenic activity against AFB1.

Aflatoxin B1↗
PubMed2005

CYP2K6 from zebrafish (Danio rerio): cloning, mapping, developmental/tissue expression, and aflatoxin B1 activation by baculovirus expressed enzyme.

A full-length zebrafish (Danio rerio) cytochrome P450 (CYP) 2K6 cDNA, was obtained (GenBank accession No. AF283813) through polymerase chain reaction cloning using degenerated primers based on a consensus CYP2 sequence and the heme-binding domain. This first CYP2K family member cloned from zebrafish had 1861 bp which contained 27 bp of 5'-untranslated region (5'-UTR), an open reading frame (ORF) of 1518 bp, and a 300 bp 3'-UTR with a poly A tail. The deduced 506 amino acid sequence of CYP2K6 had 63%, 62% and 59% identity with rainbow trout CYP2K1, CYP2K4 and CYP2K3, respectively; and 45%, 42%, and 42% identity with rabbit CYP2C1, human CYP2C19 and mouse CYP2C39, respectively. CYP2K6 mapped to 107.49cR on LG3 using the LN54 radiation hybrid panel. Its mRNA was detected at 5 days post-fertilization and in the adult liver and ovary among nine tissues examined. The ORF, including the 27 bp of the 5'-UTR, was cloned into pFastBac donor vector and then transferred into the baculovirus genome (bacmid DNA) in DH10Bac competent cells. The recombinant bacmid DNA was used to infect Spodoptera frugiperda insect cells to express the CYP2K6 protein (Bv-2K6). As its ortholog, rainbow trout Bv-2K1 [Yang, Y.H., Miranda, C.L., Henderson, M.C., Wang-Buhler, J.-L., Buhler, D.R., 2000. Heterologous expression of CYP2K1 and identification of the expressed protein (Bv-2K1) as lauric acid (omega-1)-hydroxylase and aflatoxin B1 exo-epoxidase. Drug Metab. Disp. 28,1279-83.], Bv-2K6 also catalyzed the conversion of aflatoxin B1 (AFB1) to its exo-8,9-epoxide as assessed by the trapping of a glutathione (GSH) adduct in the presence of a specific mouse alpha class glutathione S-transferase. The identity of the AFB1-GSH adduct was verified by liquid chromatography-mass spectrometry (LC-MS) and mass spectrometry-mass spectrometry (MS-MS) analysis. Although rainbow trout Bv-2K1 was capable of oxidizing lauric acid, zebrafish Bv-2K6 protein showed no activity against this substrate.

Aflatoxin B1↗
PubMed1992

[Detection of aflatoxin B1 in tissues of free-living game animals (Lepus europaeus, Phasianus colchicus, Capreolus capreolus, Anas platyrhynchos)].

This contribution states concentrations of products of toxogenic mould fungus Aspergillus in livers, kidneys and testes of specific game animals. In hares (Lepus europaeus), there was determined an average concentration in livers of 0.407 microgram.kg-1 +/- 0.29, in kidneys 0.658 microgram.kg-1 +/- 0.60, in testes 0.523 microgram.kg-1 +/- 0.27 and in the ovaries 0.207 microgram.kg-1 +/- 0.19. Higher values were found in those animals with silage pits, hayricks and liquid manure pits nearby. In roe deer (Capreolus capreolus), average concentration of Aflatoxin showed the following results:livers--0.696 microgram.kg-1 +/- 0.59, kidneys--0.794 microgram.kg-1 +/- 0.48, testes--0.367 microgram.kg-1 +/- 0.22. The different values found in the organs are likely to be dependent upon the varying resistance of species when digesting, and also upon the wide-spread variance of intaken food. Average concentration of Aflatoxin B1 in pheasants (Phasianus colchicus) were recorded to be in livers 0.329 micrograms.kg-1 +/- 0.38, and in kidneys 0.676 micrograms.kg-1 +/- 0.59. Controlled contents of mycotoxin in livers of mallards (Anas platyrhynchos) was found to be 0.840 micrograms.kg-1, in kidneys 0.594 micrograms.kg-1 +/- 0.85. Animals living in ecologically strained localities showed maximum values of 3.605 micrograms.kg-1 in kidneys and 2.484 micrograms.kg-1 in livers. An alimentary and inhalatory path for mycotoxin or for solely mould fungus into the organism could be found in the rearing of chicken. Detection of Aflatoxin B1 was performed by the means of proved radioimmunological screening method (33) that had been accompanied by routine chromatographic methods.

Aflatoxin B1↗
PubMed2006

Quantitative analysis and chronic dosimetry of the aflatoxin B1 plasma albumin adduct Lys-AFB1 in rats by isotope dilution mass spectrometry.

Aflatoxin B1 (AFB1) is a major risk factor in the pathogenesis of liver cancer in Asia and sub-Saharan Africa. Biomarkers reflecting exposure will facilitate disease risk assessment and the efficacy of protective interventions in these populations. The Lys-AFB1 adduct in plasma albumin is a candidate biomarker for this role. Although aflatoxin albumin adducts are most frequently measured in epidemiological studies using an enzyme-linked immunosorbent assay, a more specific and 10-fold more sensitive isotopic dilution mass spectrometric assay for Lys-AFB1 has recently become available. Here, the dosimetry of chronically administered AFB1 at lower doses than have been previously studied was explored using this assay. AFB1 was administered to rats for nine consecutive days at eight dose levels ranging from 50 pg to 55 microg/kg body wt. Plasma samples were enzymatically digested and processed by solid phase extraction. Lys-AFB1 was isolated by HPLC and detected via selected reaction monitoring. The dose-response relationship was linear-quadratic exhibiting upward curvature at higher doses. The adduct yield [(pg Lys-AFB1/mg albumin)/(microg AFB1/kg body wt)] increased nonlinearly with the dose by 6-fold between the 0.05 and 55 microg AFB1/kg body wt groups and exhibited the onset of saturation in the highest dose group where the adduct yield was approximately 2%. Incomplete knowledge of the timing of exposure and the complexity of the underlying biology confound the precise determination of prior AFB1 exposures in humans; however, the dosimetry of AFB1 observed in chronically dosed rats conceptually suggests that measurements in humans may underestimate exposure if a constant fraction of the AFB1 dose, approximately 2%, is assumed to be converted to Lys-AFB1 without regard to the dose.

Aflatoxin B1↗
PubMed1990

Expression of immunoreactive glutathione S-transferases in hepatic neoplasms induced by aflatoxin B1 or 1,2-dimethylbenzanthracene in rainbow trout (Oncorhynchus mykiss).

The expression of immunoreactive glutathione S-transferase (GST) was examined in hepatic neoplasms induced in rainbow trout by aflatoxin B1 (AFB) or 1,2-dimethylbenzanthracene (DMBA). Tumors were induced in adult trout by continuous dietary exposure to 8 p.p.b. AFB1 for 12 months or embryo bath exposure to DMBA (5 p.p.m. for 24 h, 3 times with 12 h intervals between exposures). Polyclonal antiserum specific for the two major trout hepatic GST subunits in trout liver was produced by immunizing rabbits with affinity-purified trout GST. Hepatocellular, cholangiolar and mixed neoplasms as well as foci of hepatocellular alteration were examined for GST immunoreactivity by the PAP technique. The majority of lesions were GST-deficient (AFB treated, 67%; DMBA treated, 54%), whereas GST expression was induced in 21% (AFB treated) and 31% (DMBA treated) of altered hepatic foci. The GST-induced foci were consistently small (AFB treated, 0.07 +/- 0.05 mm2; DMBA treated, 0.02 +/- 0.01 mm2) and none had progressed beyond the altered focus stage. The majority of larger advanced lesions (adenomas and carcinomas) were GST deficient (AFB treated, 2.33 +/- 0.35 mm2; DMBA treated, 2.95 +/- 0.59 mm2). These studies demonstrate that induced GST expression occurs in some small populations of hepatocytes, but not in larger advanced stages of malignant progression of aflatoxin- or PAH-induced hepatic neoplasms in rainbow trout.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1978

Aflatoxin B1 influence on excised soya-bean root growth, 14C-leucine uptake and incorporation.

The present work reports a portion of our continuing effort to determine the mechanism(s) whereby aflatoxins cause toxic responses in in vitro cultured plant tissues. Few investigations have dealt with the mode of action of aflatoxin B1 (AFB1) in excised plant tissues. Here is detailed AFB1 influence on growth, uptake and incorporation of 14C-leucine by excised, incubated soya-bean roots. Pure AFB1 was added to culture medium prior to autoclaving. One gram fresh weight portions of roots from three-day old soya-bean seedlings were excised and incubated for 4, 8, 12 and 24 hours. Growth was assayed by following changes in root dry weight. Aflatoxin B1 inhibited root dry weight at both 20 and 30 micrograms/ml. Uptake of 14C-leucine was checked by following its depletion from the medium. Reduced 14C-leucine uptake by roots exposed to 20 micrograms/ml AFB1 suggests that the toxin may alter the plasmalemma. A possible role for AFB1 in modification of membrane-associated amino acid transport mechanisms is discussed. Incorporation of 14C-leucine into trichloroacetic acid-precipitable cytoplasm was assayed. Inhibition of this incorporation at 20 micrograms/ml AFB1 was most apparent at 12 hours. Thus, AFB1 may also impair the ability of excised soya-bean roots to carry out protein synthesis.

Aflatoxins↗