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PubMed1997

Effects of aflatoxin B1 on liver microsomal enzymes in different strains of chickens.

Administration of Aflatoxin B1 (AFB1) with safflower seed oil to hubbard chickens caused a significant increase in liver microsomal protein, electron transport components, and drug metabolizing enzymes. No alteration was observed in the activity of alanine and aspartate aminotransferases. AFB1 treatment with dimethylsulfoxide (DMSO) as a vehicle caused a significant decrease in electron transport components, drug metabolizing enzymes, and a significant increase in the activity of aspartate aminotransferase. Higher inhibition was observed at 1.5 mg/kg dose level of AFB1. Inhibition by AFB1 was maximal after 24 hr of treatment and decreased thereafter. AFB1 treatment with DMSO caused no significant change in electron transport components and drug metabolizing enzymes in Rhode Red Island (RRI) strain. Vancob male chickens showed significant decrease in electron transport components and drug metabolizing enzymes, while a significant increase was observed in vancob females. Results suggest that the effects of AFB1 depend on treatment vehicle, strain and sex of chickens.

Aflatoxin B1↗
PubMed1999

In vitro suppressive effect of aflatoxin B1 on murine peritoneal macrophage functions.

We examined the immunosuppressive effects of aflatoxin B1 (AFB1), a toxic compound produced by the Aspergillus flavus, on murine peritoneal macrophages after in vitro pre-exposure. When thioglycollate-elicited macrophages pre-exposed to AFB1 were stimulated with lipopolysaccharide (LPS), antitumor activity induced by LPS was suppressed by 10 and 50 microM AFB1. In addition, the production of reactive intermediates including nitric oxide (NO), superoxide anion and hydrogen peroxide which have been known to be implicated in macrophage-mediated cytotoxicity, was decreased by AFB1 pretreatment in a dose-dependent manner. We also determined whether the macrophage-mediated cytokine production was altered by AFB1 in vitro pretreatment. AFB1 markedly inhibited TNF-alpha interleukin-1 (IL-1) and IL-6 production by LPS-stimulated macrophages. Taken together, these data indicate that AFB1 inhibits the killing ability of murine macrophages, decreases various secretory molecules in those cells and the macrophages would be one of many systems affected by AFB1.

Aflatoxin B1↗
PubMedDate not supplied

Comparative acute and combinative toxicity of aflatoxin B1 and T-2 toxin in animals and immortalized human cell lines.

Aflatoxin B1 (AFB1) and T-2 toxin (T-2) are important food-borne mycotoxins that have been implicated in human health and as potential biochemical weapons threats. In this study the acute and combinative toxicity of AFB1 and T-2 were tested in F-344 rats, mosquitofish (Gambusia affinis), immortalized human hepatoma cells (HepG2) and human bronchial epithelial cells (BEAS-2B). Preliminary experiments were conducted in order to assess the acute toxicity and to obtain LD50, LC50 and IC50 values for individual toxins in each model, respectively. This was followed by testing combinations of AFB1 and T-2 to obtain LD50, LC50 and IC50 values for the combination in each model. All models demonstrated a significant dose response in the observed parameters to treatment. The potency of the mixture was gauged through the determination of the interaction index metric. The results of this study demonstrate that these two toxins interacted to produce alterations in the toxic responses generally classifiable as additive; however, a synergistic interaction was noted in the case of BEAS-2B. It can be gathered that this combination may pose a significant threat to public health and further research needs to be completed addressing alterations in metabolism and detoxification that may influence the toxic manifestations in combination.

Aflatoxin B1↗
PubMed1998

The fate and acute toxicity of aflatoxin B1 in the mastomys and rat.

The fate and acute toxicity of aflatoxin B1 (AFB1) were studied in the mastomys (Praomys coucha) and compared with Fischer rats. The experiment regarding the fate of [3H]AFB1 showed that the radioactivity was excreted mainly through the feces, more rapidly in the mastomys than in the rat, regardless of whether [3H]AFB1 was given orally or intravenously. The levels of radioactivity bound to the liver DNA were lower in the mastomys than in the rat, indicating that the levels of AFB1 binding to the macromolecules in the liver were lower in the mastomys. Consistent with such differences in the fate of AFB1 between the two species, the mastomys were far more resistent to the acute effects of AFB1 than were the rats. Oral administration of AFB1 at a dose of 1.0 mg/kg to rats caused marked microscopic changes in the liver, involving hepatic necrosis and proliferation of bile ducts, but at a dose of 4.0 mg/kg to mastomys caused no pathological changes in the liver or kidneys, and at a dose of 10.0 mg/kg caused only glycogen deposition in hepatic cells in a limited area. The observed differences in susceptibility to the toxic effects of AFB1 and in the fate of AFB1 between the two species are in accord with our previous finding that liver cytosol in the mastomys inhibits microsome-mediated AFB1-DNA binding in vitro more strongly than in rat liver.

Aflatoxin B1↗
PubMed1995

Effect of dietary restriction on glutathione S-transferase activity specific toward aflatoxin B1-8,9-epoxide.

Dietary restriction (DR) reduced the metabolic activation of aflatoxin B1 (AFB1) in rats. This reduction may be attributed to the decrease of cytochrome P-450-mediated AFB1 epoxidation and/or increase in the detoxification of AFB1 catalyzed by hepatic glutathione S-transferase (GST) and other phase II detoxification enzymes. In this study the effect of DR on male rat liver cytosolic GST activity toward AFB1-8,9-epoxide was studied. The chemically-synthesized AFB1-8,9-epoxide was used as the substrate in this assay, and the formation of AFB1-GSH conjugate was analyzed by HPLC. Male Fischer 344 rats fed DR diets (60% of the food consumption of ad libitum (AL)-fed rats) showed a 2.4-fold increase in GST activity when AFB1-epoxide was used as the substrate. The results from the enzyme kinetic study showed that DR increased Vmax of the liver cytosolic GST but not the Km. Acute DR has little or no impact on GST activity when 1-chloro-2,4-dinitrobenzene and 2,4-dichloronitrobenzene were used as substrates. The mouse liver GST activity toward AFB1-epoxide was 3-fold greater than that of phenobarbital-induced rats, 4.5-fold greater than DR rats, and 14.7-fold greater than the GST activity of AL rats. This direct assay of liver GST activity using AFB1-epoxide as the substrate is useful for studying AFB1-induced biomarkers, such as AFB1-GSH conjugation and AFB1-DNA adducts.

Aflatoxin B1↗
PubMed1994

Oxidative metabolism of aflatoxin B1 by lipoxygenase purified from human term placenta and intrauterine conceptal tissues.

Aflatoxin B1 (AFB1) is a teratogen in rodents and may be a human transplacental carcinogen. Although the presence of DNA adducts of AFB1 in the human placentas has been noted, the enzyme(s) responsible for the bioactivation was not identified. In this investigation, the linoleic acid (LA)-dependent cooxidation of AFB1 catalyzed by lipoxygenase (LO) purified by Con A affinity chromatography from the term placentas of nonsmokers was studied. HPLC chromatograms detected the presence of 5- and 15-HETE as the major metabolites and 12-HETE as a minor metabolite upon incubation of arachidonic acid (AA) with affinity purified human term placental LO. These results suggest that a mixture of LO isozymes is present in the affinity-purified enzyme preparations of term placentas. The optimal assay conditions to observe maximum rate of epoxidation included incubation of 250 microM AFB1 with 80 micrograms LO and 3.5 mM LA at pH 7.2. AFB1-8,9-tris-diol produced in the reaction was estimated spectrofluorimetrically. A Vmax of 432 +/- 26 pmol of AFB1-8,9-tris diol produced/min/mg protein and a Km of 77 microM for AFB1 were observed. The AFB1-8,9-tris-diol formation was dependent on the incubation time, concentration of enzyme protein, AFB1, and LA. LO catalyzed epoxidation of AFB1 was inhibited by NDGA, BHT, BHA, ETI, and gossypol. The evidence presented here clearly demonstrates that placental LO is capable of epoxidation of AFB1. Similar results were observed with LO preparations of human intrauterine conceptal tissues at 8-10 weeks of gestation.

Aflatoxin B1↗
PubMed1984

Inhibition of oxygen uptake in liver slices of three mammalian species (rat, rabbit, guinea-pig) by aflatoxin B1 (AFB1).

Oxygen uptake in liver slices of rats, rabbits and guinea pigs were determined manometrically in the presence of different concentrations of aflatoxin B1 (AFB1). AFB1 inhibited oxygen uptake at all concentrations of AFB1 tested (3.2 microM, 16.0 microM, 48.1 microM, 64.1 microM, 80.0 microM, 112.2 microM). Inhibition was directly proportional to the concentration of AFB1 inducing the inhibition. The degree of inhibition of oxygen uptake in the 3 mammalian species seems to correlate with their respective susceptibilities to AFB1 toxicity. The highest inhibition was in guinea pig and the least in rat; that in the rabbit was intermediate between rat and guinea pig.

Aflatoxin B1↗
PubMed2005

Lack of the effect of mycotoxins-aflatoxin B1 and ochratoxin A on some functions of rat adipocytes.

Mycotoxins-aflatoxin B1 (AFB1) and ochratoxin A (OTA)-compounds which are strong carcinogenic, mutagenic and cytotoxic factors-are also known to evoke a decrease of food intake and body weight gains. The purpose of our study was to determine the direct influence of AFB1 and OTA incubated with isolated rat fat cells on the lipogenesis, lipolysis and leptin secretion. Adipocytes were isolated from the epididymal fat tissue by the collagenase digestion. Toxins used at concentrations 1, 10 and 100 microM were incubated for 90 min with adipocytes. Basal and insulin-stimulated lipogenesis-determined by the measure of [U-14C]glucose conversion to total lipids-was abated by AFB1 only at the highest concentration. At two lower ones, AFB1 did not affect the process. OTA at all used concentrations decreased insulin-stimulated lipogenesis but the effect was not dose-dependent. The lipolysis was determined by the measure of glycerol release from adipocytes. The basal lipolysis was unchanged by both toxins. The epinephrine-stimulated lipolysis was intensified by AFB1 only at the highest concentration, however, the process was not altered by OTA. The antilipolytic action of insulin was unaffected by both compounds (10 microM). To determine the influence of the tested toxins on leptin secretion, adipocytes were incubated for 120 min in the presence of glucose and insulin as stimulators of hormone secretion. AFB1 and OTA added to the incubation medium (1, 10 and 100 microM) had no significant influence on the leptin release. The results obtained in this experiment demonstrate that adipocytes are susceptible to the direct action of AFB1 and OTA. This susceptibility is, however, rather weak and is exhibited by a slight restriction of the lipogenesis (in the case of both toxins) and by a slight increase of the lipolysis (in the case of AFB1).

Adipocytes↗
PubMed1980

A high pressure liquid chromatography study on the removal of DNA-bound aflatoxin B1 in rat liver and in vitro.

Following intraperitoneal administration of [3H] aflatoxin B1 (AFB1) to young adult male rats, there is rapid uptake of the carcinogen by the liver, the target organ for carcinogenesis, leading to DNA covalent binding. Acid hydrolysis of this DNA shows that after 2h, the major DNA adduct is trans 8,9-dihydro-8-(7-guanyl)-9-hydroxy AFB1 (AFB1-gua). By 24h after AFB1 administration the major DNA adduct is no longer AFB1-gua but a product with the identical retention time on h.p.l.c. to 8,9-dihydro-8-(N5-formyl-2',5',6' triamino-4' oxo-N5-pyrimidyl)-9-hydroxy AFB1 (AFB1-triamino-Py). 48h after carcinogen administration, only a small amount of AFB1-gua remains and the major product is AFB1-triamino-Py. The half-life of removal of AFB1-gua is 22h, while AFB1-triamino-Py is much more persistent. In vitro incubation studies on DNA isolated from rats treated 2h previously with [3H] AFB1 show that at pH 7.4 AFB1-gua is the major product released from the DNA with some release of 8,9-dihydro-8,9-dihydroxy AFB1, (AFB1-diol). If more extensively reacted AFB1-DNA is used than that obtained from in vivo administration, then the rate of AFB1-diol release is enhanced while that of AFB1-gua is reduced. It would appear, therefore, that much of the release of AFB1 from DNA in vivo within the first 24h is probably not through a DNA repair process but through chemical release arising from the positively charged N7-guanine. There is considerable conversion of AFB1-gua to AFB1-triamino-Py on in vitro incubation of DNA as well as AFB1-gua and AFB1-diol release. By 24h approximately 66% of the bound AFB1 is in the form of AFB1-triamino-Py and after 48h the conversion is complete. The complex pattern of AFB1-release from DNA may have important consequences in both the induction of mutations and in tumour initiation.

Aflatoxin B1↗
PubMedDate not supplied

[Effect of the type of nutrition and aflatoxin B1 on the structure of chromosomes].

Deficiency of the essential nutrients lysine, methionine, threonine and vitamins A, E, C significantly increases the mutagenic environment of somatic cells in growing Wag rats. Aflatoxin B1 produces a pronounced mutagenic effect on the cellular genetic apparatus; this effect is substantially modified due to the nutrition character: it is either intensified or inhibited. The results obtained suggest that the nutritional factors can de used for prevention and elimination of aflatoxin B1-induced mutations.

Aflatoxin B1↗
PubMed1981

Excretion of aflatoxin B1 as a glutathione conjugate.

Intraperitoneal injection of 3H - GSH (15.4 mg, 0,5 microCi) 15 minutes before a similar i.p. treatment with Aflatoxin B1 (AFB1) (2mg/kg) showed less than 40% of the radioactivity in the 24 h urine and 30-35% in the bile. Analysis of the urine and bile samples by TLC and separation with XAD-2, showed only traces of the AFB1 - GSH adduct present in the urine and 14% in the bile, AFB1 metabolites isolated from the urine of the 3H - GSH treated rats identical with those of rats treated with AFB1 only. While GSH Conjugate appears therefore to be a major component of biliary excretion of AFB1, it does not seem to be significant in the urinary excretion of the toxin.

Aflatoxin B1↗
PubMed1990

Tumor dose-response studies with aflatoxin B1 and the ambivalent modulator indole-3-carbinol: inhibitory versus promotional potency.

Indole-3-carbinol (I3C), a natural compound from cruciferous vegetables, inhibits aflatoxin B1 (AFB1) carcinogenesis in trout when administered prior to and during carcinogen exposure, but also promotes it in the same species when given after AFB1 initiation. To provide quantitative potency information for these opposing activities, detailed tumor dose-response studies were performed with AFB1 (10-400 ppb) and I3C (0-4,000 ppm). In a plot of (logit) percent tumor response vs log AFB1 exposure, the results generated a series of parallel AFB1 dose-response curves. Increasing I3C doses displaced these curves, respectively, toward higher and lower AFB1 doses in the inhibition and promotion studies. Similar potencies were observed over the dose range 0-1,500 ppm I3C; the 50% promotion and inhibition (P50 and I50) values were 1,000 vs 1,400 ppm I3C, respectively. Differences in the protocols used in the two studies suggest that the inhibitory activity of I3C is more likely to supersede promotion under human exposure conditions.

Aflatoxin B1↗
PubMed1983

Relation between geographical distribution of liver cancer and climate-aflatoxin B1 in China.

This paper analyses, for the first time in China, the relationship between the data on climate (temperature and humidity) in the country, aflatoxin, hepatitis B and primary liver cancer mortality, by using the methods of geographical epidemiology and generalized factor analysis, and also approaches the characteristics of the geographical distribution of liver cancer in China from a climate-mould viewpoint. The authors come to the conclusion that climate is an important environmental condition that determines the differences in the distributions of liver cancer in different areas, and that aflatoxin B1 is one of the main carcinogenic factors of liver cancer.

Aflatoxin B1↗
PubMed1998

Refined structure of the doubly intercalated d(TATAFBGCATA)2 aflatoxin B1 adduct.

The refined solution structure for the 8, 9-dihydro-8-(N7-guanyl)-9-hydroxyaflatoxin B1 adduct was refined from the oligodeoxynucleotide duplex d(TATAFBGCATA)2 using a molecular dynamics protocol restrained by NOE data obtained from 1H NMR and compared with the refined structure of the unmodified oligomer, d(TATGCATA)2. The two aflatoxin B1 (AFB1) moieties were symmetry related by the pseudodyad axis of the self-complementary oligodeoxynucleotide. Each AFB1 intercalated into the helix above the 5'-face of the modified guanine, corroborating NMR spectroscopic data [Gopalakrishnan, S., Harris, T. M., and Stone, M. P. (1990) Intercalation of Aflatoxin B1 in Two Oligodeoxynucleotide Adducts: Comparative 1H NMR Analysis of d(ATCAFBGAT).d(ATCGAT) and d(ATAFBGCAT)2 Biochemistry 29, 10438-10448]. Molecular dynamics calculations restrained with 292 experimentally and empirically derived distances refined a family of structures characterized by pairwise root mean square differences of <1.3 A. Complete relaxation matrix calculations yielded a sixth root residual of 11 x 10(-2). Comparison of the refined structure with that of the corresponding unmodified oligodeoxynucleotide suggested that the two AFB1 adducts introduced a perturbation of the DNA localized at the two sites of adduction. The calculations predicted that each adduct introduced a "kink" into the DNA helical axis. However, the pseudodyad symmetry relating the two intercalation sites resulted in no net bending of the DNA. The results suggest the possibility that AFB1 lesions at adjacent guanines in the 5'-GC-3' sequence may be recognized or processed differently than are isolated AFB1 lesions.

Aflatoxin B1↗
PubMed1988

The binding of aflatoxin B1 to rat liver nuclear proteins and its effect on DNA-dependent RNA synthesis.

This paper reports studies on the binding of aflatoxin B1 (AFB1) to rat liver nuclear proteins in vivo and in vitro, and its effect on RNA synthesis. Two hours after rats (200 g) were given a single i.p. injection of 300 micrograms AFB1 containing 50 microCi [3H]AFB1/100 g body wt, AFB1 was found bound to the free nuclear proteins (29.7 pmol/mg protein), histones (20.3 pmol/mg protein) and chromatin-bound non-histone proteins (13.8 pmol/mg protein). The binding of AFB1 to histones was further studied in vitro. We found that for a given type of histone, the binding level varied greatly depending on the conditions used. Under both in vivo and in vitro conditions, however, H3 was always the most efficient substrate, and H4/H2B always the least efficient substrates for AFB1 binding. These results suggest that the binding preference was mainly related to the intrinsic properties of the histone type, and was little affected by the geometric arrangement of the histones in chromatin. Using nuclear proteins added to the RNA synthesizing system in vitro, we found that only the histone fraction had a strong inhibitory effect. Further studies, however, indicated that this inhibition was not due to histones per se, but rather to poly-ADP-ribosylated histones present in the histone preparations. No detectable difference in effect was found between control and AFB1-bound nuclear proteins on RNA synthesis. Moreover, higher levels of AFB1 binding to histones did not potentiate the inhibitory effect. We therefore conclude, and in direct support to our previous correlation studies (see the preceding paper), that the binding of AFB1 to nuclear proteins has no inhibitory effect on RNA synthesis.

Aflatoxin B1↗
PubMed1989

Carcinogen-nucleic acid interactions: equilibrium binding studies of aflatoxin B1 with the oligodeoxynucleotide d(ATGCAT)2 and with plasmid pBR322 support intercalative association with the B-DNA helix.

Equilibrium binding of aflatoxin B1 (AFB1) to the oligodeoxynucleotide d(ATGCAT)2 was examined by using 1H NMR. AFB1 binds to double-stranded d(ATGCAT)2 with an apparent binding constant of 3.7 x 10(3) M-1. The equilibrium is rapid on the NMR time scale; the observed 1H NMR spectrum represents the population-weighted average of the chemical shifts arising from the free and bound states of the oligodeoxynucleotide and the AFB1. The spectrum of d(ATGCAT)2 exhibits exchange broadening in the presence of AFB1, manifested as decreases in apparent T2 relaxation times for the d(ATGCAT)2 base protons. Upon binding to d(ATGCAT)2, the AFB1 signals are shifted upfield, indicative of increased shielding. The adenine H2 protons are also shifted upfield in the presence of the carcinogen. Small changes in chemical shift are observed for other d(ATGCAT)2 protons. A substantial decrease in the nonselective T1 relaxation time is observed for the adenine H2 protons in the presence of AFB1. Competition binding experiments in which the competing ligands actinomycin D, ethidium bromide, and spermidine were individually added to an AFB1-d(ATGCAT)2 equilibrium mixture showed that addition of 1 equiv of actinomycin D or 4 equiv of ethidium bromide was sufficient to displace bound AFB1 from d(ATGCAT)2. In contrast, the addition of spermidine did not result in the displacement of bound AFB1 molecules and may have slightly enhanced binding, presumably due to stabilization of the DNA duplex. 1H NOESY experiments confirmed that the overall conformation for the d(ATGCAT)2 duplex was right-handed both in the absence and in the presence of AFB1. Equilibrium binding of AFB1 to d(ATGCAT)2 is greatly diminished at higher temperatures at which the oligodeoxynucleotide is single-stranded.(ABSTRACT TRUNCATED AT 250 WORDS)

Aflatoxin B1↗
PubMed2001

Identification of homozygous deletions at chromosome 16q23 in aflatoxin B1 exposed hepatocellular carcinoma.

Loss of heterozygosity (LOH) represents the most frequent genetic alteration observed in hepatocellular carcinoma (HCC). Chromosome 16q is of particular interest as it exhibits LOH in 29% of HCC tumors and is frequently lost in breast, prostate, ovarian and gastric carcinomas. We genotyped 157 HCC tumors for 17 microsatellite markers distributed on chromosome 16q and determined a common region of LOH localized between the markers D16S518 and D16S504. By refining the boundaries of two interstitial LOH and two homozygous deletions, the critical region was delimited to 180 kb between D16S3096 and D16S3029. This region is located in intron 8 of the WWOX/FOR gene, but a search for mutations in all coding exons of this gene in 27 HCC tumors and cell lines did not reveal any tumor somatic alterations. Furthermore, by RT-PCR, no abnormal transcripts of this WWOX/FOR gene was detected in nine HCC cell lines. Finally, analysis of the p53 gene mutations with the clinical parameters of all tumors revealed that the two homozygous deletions have occurred in tumors presenting a R249S mutation. Our data revealed a relationship between chromosome 16q homozygous deletions and R249S p53 mutations in tumors where the patient had been exposed to aflatoxin B1 (P=0.002). These results are consistent with a role of aflatoxin B1 in the instability of chromosome 16q at the fragile site FRA16D. However, the nature of the specific gene that is altered during hepatocarcinogenesis remains to be elucidated.

Aflatoxin B1↗
PubMed1989

[Effect of aflatoxin B1 on DNA enzymatic methylation and secondary structures of the rat liver].

Methylation and secondary structure of DNA in rat liver versus time of aflatoxin B1 (AfB1) treatment were studied. A 50% drop in 5-methylcytosine level in liver DNA as compared with control was observed long before tumor development. Also, certain changes in DNA secondary structure were seen. The DNA changes were more pronounced in the F1 progeny of rats inoculated with AfB1 at the terminal stage of gestation.

Aflatoxin B1↗