Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Aflatoxin B1”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 937 records · Page 52Linked to original sources
PubMed1989

Metabolism of aflatoxin B1 in the bovine olfactory mucosa.

Carcinomas of the ethmoidal region of the nose are observed relatively frequently in cattle in several countries in tropical and subtropical latitudes. Viruses have been implicated as causative agents, but it has been observed that affected animals sometimes suffer from aflatoxicosis, and a role of aflatoxin B1 (AFB1) in the aetiology has also been proposed. We have examined whether the bovine nasal olfactory mucosa has a capacity to metabolize AFB1. The contents of cytochrome P-450 and cytochrome b5, and the NADPH cytochrome c reductase activity in the nasal olfactory mucosa have also been determined. Comparative experiments have been performed with the liver. Incubations with 3H-labelled AFB1 showed that the nasal olfactory mucosa has a much higher capacity than the liver to form lipid-soluble, water-soluble and tissue-bound AFB1-metabolites. High-resolution microautoradiography showed a strong localization of tissue-bound metabolites in the sustentacular cells in the apical portion of the olfactory surface epithelium and in Bowman's glands in the olfactory lamina propria mucosae. Especially in the sustentacular cells the labelling was preferentially located in the nuclei of the cells. Liquid chromatography of chloroform extracts of the nasal olfactory mucosa and the liver incubated with 3H-AFB1 showed formation of several metabolites. The dominating peak in both tissues was aflatoxin M1 (AFM1). However, the amount of AFM1 was higher in the nasal olfactory mucosa than in the liver, and the amounts and proportions of several other metabolites also differed markedly between the two tissues. The level of cytochrome P-450 in the nasal olfactory mucosa was found to be about one quarter of that in the liver, but the NADPH cytochrome c reductase activity was much higher in the nasal olfactory mucosa than in the liver. In addition, the cytochrome b5: cytochrome P-450 ratio was higher in the nasal olfactory mucosa than in the liver. The higher metabolism of AFB1 in the nasal olfactory mucosa than in the liver may be related to differences in the cytochrome P-450 isoenzyme profile. In addition, the microsomal electron transport to cytochrome P-450 may be facilitated by the high reductase: cytochrome P-450 ratio and the high cytochrome b5: cytochrome P-450 ratio in the nasal olfactory mucosa.(ABSTRACT TRUNCATED AT 400 WORDS)

Aflatoxin B1↗
PubMed1995

Natural co-occurrence of Fusarium toxins and aflatoxin B1 in corn for feed in north Vietnam.

Natural occurrence of Fusarium mycotoxins (trichothecenes and fumonisins) and aflatoxin B1 (AFB1) were surveyed in 32 corn samples, harvested in 1993 and randomly sampled in 1994 in several districts of Hanoi, Vietnam. Corn samples were first milled into fine powder, extracted with methanol-water (3:1) and the crude extracts obtained from the same samples were used for the simultaneous analysis of the trichothecenes such as nivalenol (NIV), deoxynivalenol (DON), and T-2 toxin (T-2) by gas chromatography/mass spectrometry (GC/NS); fumonisins B1 (FB1), B2 (FB2), and B3 (FB3) by high-performance liquid chromatography (HPLC) with a flourescence detector; and AFB1 by and ELISA kit based on a monoclonal antibody. The data revealed that 14, 8, 4, 3, and 2 out of 15 corn kernel samples were positive for AFB1, FB1, FB2, FB3, and NIV with the average levels being 28, 1, 101, 276, 232, and 858 ppb, respectively, and neither DON nor T-2 were detected. As for the other 17 samples of corn powder, 13, 15, 12, 10, 4 and 2 were positive for AFB1, FB1, FB2, FB3, DON, and NIV with the average being 30, 780, 289, 176, 3, 170, and 1,365 ppb, respectively, and T-2 was not detected. Although their positive rates and levels fell in the ranges reported elsewhere, it was found for the first time that the Fusarium toxins (NIV, DON, and fumonisins) and an Aspergillus toxin (AFB1) were naturally co-contaminated in selected samples of corn produced in north Vietnam.

Aflatoxin B1↗
PubMed2003

Kinetics of adsorption and desorption of aflatoxin B1 by viable and nonviable bacteria.

The reactions involved in the binding (adsorption) and release (desorption) of aflatoxin B1 (AFB1) to and from the surface of bacteria were investigated. Viable and heat-killed Lactobacillus rhamnosus GG, L. rhamnosus LC-705, and Propionibacterium freudenreichii subsp. shermanii JS were incubated in phosphate-buffered saline containing variable concentrations (0.0017 to 13.3 microg/ml) of AFB1. The relationship between the bacterial surface hydrophobicity and the AFB1 adsorption affinity was also investigated. A linear relationship was observed between the specific rate of AFB1 adsorption and the AFB1 concentration for all bacteria. The nature of desorption of adsorbed AFB1 was investigated by repetitive aqueous washes. A linear relationship was observed between the natural log value of the concentration of AFB1 adsorbed and the number of washes for all bacteria studied. The desorption constants were strain-dependent and were lower for heat-killed bacteria than for viable bacteria. Heat treatment appears to alter the surface properties of the bacteria rather than expose new adsorption sites. No correlation was found between the hydrophobicity and the AFB1 adsorption affinity.

Adsorption↗
PubMed1991

Tissue disposition and excretion of 14C-labelled aflatoxin B1 after oral administration in channel catfish.

The pharmacokinetics, tissue distribution and excretion of 14C-labelled aflatoxin B1 (AFB1) were examined after oral administration (250 micrograms/kg body weight) in channel catfish (Ictalurus punctatus). Plasma concentrations of parent AFB1 were best described by a one-compartment pharmacokinetic model, in which peak plasma concentration (503 ppb) occurred at 4.1 hr after dosing. The absorption and elimination half-lives were 1.5 and 3.7 hr, respectively. AFB1 was highly bound (95%) to plasma proteins. Concentrations of 14C (in AFB1 equivalents) measured in the tissues were highest at 4 hr, ranging from 596 ppb in the plasma to 40 ppb in the muscle. AFB1 residues were rapidly depleted; at 24 hr the concentrations in the plasma and muscle were 32 and less than 5 ppb, respectively. Concentrations in the bile exceeded 2000 ppb (at 24 hr), whereas the highest concentration in the urine was 51 ppb (4-6-hr collection interval). Renal and biliary excretion accounted for less than 5% of the administered dose, indicating incomplete absorption. Pharmacokinetic modelling and tissue data demonstrate a very low potential for the accumulation of AFB1 and its metabolites in the edible flesh of channel catfish through the consumption of AFB1-contaminated feed.

Administration, Oral↗
PubMed1994

Induction of specific cytochrome P450s involved in aflatoxin B1 metabolism in hepatitis B virus transgenic mice.

The relative roles of hepatitis B virus (HBV) and aflatoxin and their possible mechanism of interaction in the etiopathogenesis of hepatocellular carcinoma (HCC) are not understood. One hypothesis is that viral infection and associated liver injury alter expression of carcinogen-metabolizing enzymes. We tested this hypothesis in an HBV-transgenic mouse model in which a synergistic interaction occurs between aflatoxin B1 (AFB1) and HBV in the induction of HCC (Sell et al., Cancer Res 51:1278-1285, 1991). In this transgenic mouse lineage, overproduction of the HBV large envelope protein results in progressive liver cell injury, inflammation, and regenerative hyperplasia. Initially, two cytochrome P450s of importance in AFB1 metabolism in the mice were identified, namely Cyp2a-5 and Cyp3a, using specific antibodies and chemical inhibitors. The expression of these P450 isoenzymes and an alpha-class glutathione S-transferase (GST) isoenzyme, YaYa, were examined. Increased expression and altered distribution of Cyp2a-5 were demonstrated, by immunohistochemical analysis, to be associated with the development of liver injury in mice and to increase with age between 1 and 12 months. Cyp3a expression was also increased in HBV-transgenic mice, but the increase was not as clearly related to age. GST YaYa levels were the same in HBV-transgenic mice and their nontransgenic littermates of all ages. These results show that expression of specific cytochrome P450s is altered in association with overexpression of HBV large envelope protein and liver injury in this model. This may have general relevance to human HCC, the etiology of which is associated with a diverse range of liver-damaging agents.

Aflatoxin B1↗
PubMed1993

DNA binding and mutagenicity of aflatoxin B1 catalyzed by isolated rabbit lung cells.

The abilities of different rabbit lung cell types to bioactivate aflatoxin B1 (AFB1) to a DNA-binding and mutagenic metabolite have been examined. Microsomes were prepared from centrifugal elutriation-enriched preparations of isolated rabbit lung cell types. The activation of [3H]AFB1 (5.0 or 200 microM), measured indirectly as covalent binding to calf thymus DNA, was concentrated in microsomes from the non-ciliated bronchiolar epithelial (Clara) cell-rich fractions (13-22 times the activity of whole lung microsomes). Microsomes from type II cell-rich fractions had minimal activity. Significant correlations were detected between the rates of microsomal DNA binding and the percentages of Clara cells in the fractions. Prior treatment of rabbits with the cytochrome P450 class 1A inducer beta-naphthoflavone had no significant effect on the microsomal activation of AFB1. In other experiments, intact, enriched isolated rabbit lung cells were incubated with AFB1 (0-1.5 microM) in a modification of the Ames mutagenicity assay, using Salmonella typhimurium strain TA100. The ability to activate AFB1 to mutagenic metabolite(s) in this system was localized in Clara cell-rich fractions, with no significant activity being detected in other fractions. The results of these studies indicate that the biotransformation of AFB1 to DNA-binding and mutagenic metabolite(s) in rabbit lung is heterogeneous, and that the Clara cell is specifically implicated in this ability.

Aflatoxin B1↗
PubMed2000

Uptake of aflatoxin B1 and T-2 toxin by two mycotoxin bioassay microorganisms: Kluyveromyces marxianus and Bacillus megaterium.

Uptake of aflatoxin B1 (AFB1) and trichothecene T-2 toxin from growth medium by mycotoxin bioassay strains of Klutyveomyces marxianus and Bacillus megaterium was assessed by incubating, washing, and sonicating the cells, extracting samples with chloroform, and analysing the extracts by a combination of high-performance thin-layer chromatography (HPTLC) and fluorescence densitometry. Using cultures of K. marxianus, the entire AFB1 dose was recovered and no AFB1 metabolites were detected. Less than 1% of the AFB1 was recovered from the cells, and AFB1 did not inhibit growth. Methanol in the incubation medium had no significant effect on the levels of AFB1 associated with K. marxianus cells. The entire dose of T-2 toxin was also recovered from K. marxianus cultures, and no metabolites were detected; again, less than 1% of T-2 toxin was cell-associated, but growth was completely inhibited. AFB1 partially inhibited the growth of B. megaterium; approximately 12% of the dose could not be recovered, and no AFB1-related metabolites were detected. Methanol increased the levels of recoverable AFB1 associated with B. megaterium cells. In the case of T-2 toxin, around 8% of the dose was not recovered, and no metabolites were detected; growth of B. megaterium was stimulated. These results suggest irreversible binding of both toxins, or derivatives of them, to the cells of B. megaterium.

Aflatoxin B1↗
PubMed1980

Species-dependent effects of dietary lindane and/or zineb on the activation of aflatoxin B1 into mutagenic derivatives.

Sprague-Dawley rats and Swiss mice were given diets containing lindane, 125 ppm, or zineb, 5200 ppm, or a mixture of both at the above-mentioned concentrations for 2 and 4 weeks. The effect of pesticide ingestion on the ability of liver S9 to metabolize aflatoxin B1 (AFB1) into mutagenic derivatives was tested by the Salmonella (TA100)/microsome test according to Ames. Control mouse-liver S9 was less efficient (13%) than the corresponding preparation from control rat liver. The ingestion of lindane produced a similar increase in the activities of both rat- (68%) and mouse-liver S9 (62%). Pretreatment with zineb inhibited (46%) rat-liver S9 but caused a marked increase (400%) in the activity of mouse-liver S9. Concomitant exposure to both pesticides showed that lindane released the inhibitory action of zineb on rat-liver S9 and reduced the stimulatory effect of zineb on mouse-liver S9. The inducing action of zineb in mice was a function of the dietary concentration of the pesticide. No effect was observed at dietary concentrations of zineb up to and including 500 ppm.

Aflatoxin B1↗
PubMed2003

Synergistic interaction between aflatoxin B1 and hepatitis B virus in hepatocarcinogenesis.

Chronic hepatitis B virus (HBV) infection and dietary exposure to aflatoxin B1 (AFB1), two of the major risk factors in the multifactorial aetiology of hepatocellular carcinoma (HCC), co-exist in those countries with the highest incidences of and the youngest patients with this tumour, raising the possibility of a synergistic carcinogenic interaction between the two agents. Experimental studies in HBV-transgenic mice and woodchucks infected with woodchuck hepatitis virus were the first to show a synergistic hepatocarcinogenic effect between hepadnaviral infection and AFB1 exposure. With the availability of urinary and serum biomarkers that more accurately reflect dietary exposure to AFB1 than did the initially used food sampling and dietary questionnaires, cohort studies of patients with HCC in China and Taiwan have provided compelling evidence for a multiplicative or sub-multiplicative interaction between HBV and AFB1 in the genesis of human HCC. A number of possible mechanisms for the interaction have been suggested. Chronic HBV infection may induce the cytochrome P450s that metabolise inactive AFB1 to the mutagenic AFB1-8,9-epoxide. Hepatocyte necrosis and regeneration and the generation of oxygen and nitrogen reactive species resulting from chronic HBV infection increase the likelihood of the AFB1-induced p53 249ser and other mutations and the subsequent clonal expansion of cells containing these mutations. Nuclear excision repair, which is normally responsible for removing AFB1-DNA adducts, is inhibited by HBV x protein, favouring the persistence of existing mutations. This protein also increases the overall frequency of DNA mutations, including the p53 249ser mutation, and may contribute to uncontrolled cell cycling when p53 is non-functional.

Aflatoxin B1↗
PubMed1999

Temporal patterns of DNA adduct formation and glutathione S-transferase activity in the testes of rats fed aflatoxin B1: a comparison with patterns in the liver.

Fisher-344 male rats were fed 1.6 ppm of aflatoxin B1 (AFB1) continuously and intermittently for several weeks. At various time periods, DNA was isolated from the testes and livers and analyzed for AFB1-DNA adducts. The ability of the testis to detoxify AFB1 was also investigated by the glutathione S-transferase (GST) activity assay and compared with that of the liver. The levels of testicular AFB1-DNA adducts were 2.4 to 8.1 times lower than those of the liver after 4 to 16 weeks of continuous treatment and 2.2 to 46.2 times lower after 8 to 20 weeks of intermittent treatment. The testicular DNA adducts markedly decreased over time. By 16 weeks of continuous and 20 weeks of intermittent exposure, they had decreased 37 and 91%, respectively. In contrast, hepatic AFB1-DNA adducts increased four-fold from 4 to 16 weeks of continuous treatment but increased at a much slower rate after intermittent exposure. In both the liver and testis, significant levels of AFB1-DNA adducts persisted for at least 1 month after ending the treatment, suggesting that this type of lesion was poorly repaired. In control rats, the testis showed significantly higher GST activity than the liver. In treated rats, these differences were significant during the first 12 weeks of continuous treatment but not at later times. Tissue-specific differences such as germ-cell depletion and increased testicular detoxification may play an important role in the observed differential pattern of DNA adduct formation between the testis and liver.

Aflatoxin B1↗
PubMed1997

In vivo activation of aflatoxin B1 in C57BL/6N mice carrying a human fetus-specific CYP3A7 gene.

The in vivo activation of aflatoxin B1 (AFB1) was assessed by using two transgenic mouse lines, M2 and M10, in which the human fetus-specific CYP3A7 was expressed in the kidney (M2) and the liver (M10), respectively. Male mice of 8 weeks old from these two lines were treated with a single i.p. injection of AFB1 (4 mg/kg body weight). AFB1-N7-guanine adduct was quantified by high-performance liquid chromatography. DNA damage was measured using the alkaline elution technique 2 and 6 h after AFB1 treatment. Administration of AFB1 resulted in a significantly higher level of AFB1-N7-guanine in the livers of M10 transgenic mice compared with their nontransgenic littermates (16.5 +/- 4.2 versus 10.4 +/- 1.2 ng/mg DNA, P < 0.01). The level of this biomarker was also significantly higher in the kidney of the M2 mice compared with control mice (73.0 +/- 6.3 versus 50.2 +/- 9.5 ng/mg DNA, P < 0.01). Similar results were also observed with DNA damage expressed as normalized area above curve (NAAC) in the two transgenic lineages, e.g., NAAC values were significantly higher in the livers of M10 and the kidneys of M2 mice. A dose-response relationship of NAAC values was observed in the livers of M10 mice when treated with AFB1 at different doses ranging from 1 to 16 mg/kg body weight, whereas in nontransgenic mice, only slight but not statistically significant increases of NAAC values were observed. Both the mouse CYP3A11 and GST-Yc subunit were expressed at identical levels in these transgenic lines. The results of this study present further evidence that human fetuses are also under the carcinogenic attack of AFB1 as adults if exposed to this potent carcinogen.

Aflatoxin B1↗
PubMed1996

Determination of aflatoxin B1 biotransformation and binding to hepatic macromolecules in human precision liver slices.

Although epidemiological studies suggest that aflatoxin B1 (AFB1) is a human carcinogen, at least in the presence of hepatitis B virus infection, animal studies have demonstrated large differences in species sensitivity to AFB1, and the sensitivity of humans relative to experimental animals remains unclear. The purpose of this study was to determine the profile of AFB1 metabolism and the extent of AFB1 binding to cell macromolecules in human liver slices under experimental conditions that would allow direct comparison to similar endpoints in the rat, a species sensitive to the carcinogenic actions of AFB1. Liver slices were prepared from three individual human liver samples with a Krumdieck tissue slicer and incubated with 0.5 microM [3H]AFB1 for 2 hr. Significant interindividual variations were observed in the rates of oxidative metabolite formation and in specific binding to cell macromolecules. The rates of oxidative metabolism of AFB1 to AFQ1, AFP1, and AFM1 in the three human liver samples were similar to those previously observed in rat liver slices. AFB1-GSH conjugate formation was not detected in any of the human liver samples, and yet specific binding of AFB1 to cell macromolecules was considerably lower in the human liver slices relative to that in rat liver slices. AFB1-DNA binding levels ranged from 3 to 26% of control rat and AFB1-RNA binding levels ranged from 25 to 49% of control rat. The AFB1-protein binding level in the one human sample measured was 20% of that observed for control rat. While these results suggest that humans do not form as much AFBO as the rat, they are also consistent with the hypothesis that humans do not possess GST isozyme(s) with high specific activity toward AFBO. Significant individual differences in AFB1 metabolism and binding between humans suggest the presence of genetic and/or environmental factors that may confer large variability in susceptibility to AFB1.

Adult↗
PubMed1998

Modulation of aflatoxin-B1 hepatocarcinogenesis in trout by dehydroepiandrosterone: initiation/post-initiation and latency effects.

Previously, we demonstrated that dehydroepiandrosterone (DHEA) enhances aflatoxin B1 (AFB1) hepatocarcinogenesis in trout when administered following AFB1 exposure. This paper examines the effect of DHEA on tumor latency and the comparative potency for DHEA to modulate AFB1 carcinogenesis when administered prior to and concurrent with AFB1 compared with a post-initiation exposure. Trout were initiated by a 30 min water bath exposure to 10 p.p.b. AFB1. At 3 months post-initiation, animals were started on either control diet or a diet containing 444 p.p.m. dehydroepiandrosterone (DHEA). Fifty trout per treatment were sampled prior to the start of experimental diets, and then at monthly intervals for the next 7 months and examined for the presence of tumors. Tumors were not detected in initiated controls until 7 months after initiation. In initiated trout fed DHEA, the first tumor was detected 5 months after initiation (after just 2 months of dietary DHEA). At 6 months post-initiation, 20% of the AFB1-initiated trout fed DHEA had tumors, while no tumors were visible in either AFB1-initiated controls or noninitiated trout fed DHEA. A second experiment was designed to determine if the enhancing effect of DHEA on AFB1 carcinogenesis is dependent on the time of DHEA administration relative to the time of AFB1 exposure, and if DHEA could be chemopreventive if administered prior to and concurrent with AFB1. Trout were fed one of two levels of DHEA (888 or 1776 p.p.m.) either prior to and during a 4-week initiation period of dietary AFB1 administration, or for 8 weeks following initiation with AFB1. At 9 months after initiation the livers were examined for tumors. Neither exposure protocol provided protection towards AFB1 hepatocarcinogenesis. The strongest enhancement occurred when DHEA was fed during the post-initiation period. Levels of p53 and p34cdc2 were decreased by DHEA treatment, indicating that DHEA may act through alterations in cell-cycle control.

Aflatoxin B1↗
PubMed1999

Short-term moderate aflatoxin B1 exposure has only minor effects on the gut-associated lymphoid tissue of Brown Norway rats.

Aflatoxin B1 (AFB1) is toxic to the systemic immune system in various animal species, whereas little is known about its effect on the gut-associated lymphoid tissue (GALT). It may be hypothesized that the toxicity of AFB1 and its locally generated metabolites in the intestinal tissue may result in a disturbed intestinal integrity and, subsequently, in an impaired immune response towards dietary proteins. The objective of our study was to investigate the toxic effect of short-term moderate AFB1 exposure on the intestinal epithelium and on the immune cells associated with the intestinal tract. The toxicological potential of AFB1 and its metabolites to the intestinal epithelium was determined by measuring viability and genotoxic damage in isolated jejunal epithelial cells (comet assay) after 30 min incubation in vitro. In vivo toxicology studies were carried out with Brown Norway (BN) rats, which were exposed orally once a week with AFB1 (1 x 100 microg/kg body weight (b.w.)/week) for 5 consecutive weeks. Viability and genotoxicity were measured in explanted jejunal epithelial cells. For studying the effectiveness of AFB1 on immunological parameters BN rats were treated with a high (study 1: 1 x 1 mg/kg b.w./week) or a low (study 2: 1 x 100 microg/kg b.w./week) AFB1 dose for 5 consecutive weeks with or without ovalbumin (OVA). Mesenteric lymphocytes were isolated and proliferative responsiveness, secretion of interferon-gamma, and changes in lymphocyte subpopulations as well as mucosal mast cell specific protease and anti-OVA specific antibody concentrations were measured. In vitro, AFB1 ( >30 microM) induced genotoxicity in rat jejunal epithelial cells. The oral administration of AFB1 (1 x 100 microg/kg b.w./week) did not induce DNA damage in jejunal epithelial cells. The high AFB1 dose increased the number of CD8+ and CD8/CD71 + cells in mesenteric lymph nodes. The immune response towards OVA was not affected. The low AFB1 dose only reduced the proliferative responsiveness of mesenteric lymphocytes (P < 0.05). Serum concentrations of anti-OVA specific IgE antibody, of RMCPII, and the capacity of mesenteric lymphocytes to produce interferon-gamma were not impaired by AFB1. In conclusion, exposure to moderate doses of AFB1 does not damage the intestinal epithelium and has only minor effects on the GALT. The low exposure, as it may predominantly occur in western countries, does not appear to increase the risk for sensitization to dietary antigens.

Aflatoxin B1↗
PubMed2001

Aflatoxin B1 induces apoptosis in rat liver: protective effect of melatonin.

OBJECTIVES: A study of liver apoptosis after aflatoxin B1 (AFB1) administration and the effect of melatonin (MEL) was investigated in male rats. METHODS: Five groups of 15 rats each were used: controls, MEL Soln-treated rats (MEL dose,5 mg/Kg body wt), AFB1-treated rats (50 microg/Kg body wt), MEL Soln+AFB1-treated rats, and MEL micro-capsules (MEL-MC)+ AFB1-treated rats. After 8 weeks of treatment, biochemical measurements in liver homogenates and histopathological examination of liver sections of different groups using light and transmission electron microscope were done. The caspase-3 enzyme activity, apoptotic marker, was determined in liver tissues. Because hepatic antioxidants represent the major defence against toxic liver injury, and they act as anti-apoptosis. So, the levels of glutathione (GSH) and zinc (Zn) and the enzyme activities of glutathione reductase (GR), glutathione peroxidase (GSPx) and glutathione-S-transferase (GST) were determined. In addition, the levels of malondialdehyde (MDA), a lipid peroxidation product, and nitric oxide (NO) levels were measured. RESULTS: The levels of caspase-3 activities in AFB1 group were significantly higher than control group. The apoptosis was associated with degenerative and necrotic changes in the hepatocytes. Concomitantly, the levels of MDA and NO in liver tissues were significantly increased while the levels of GSH, Zn and enzyme activities of GSPx and GR in liver tissues were significantly decreased in AFB1 group compared to their levels in controls. Caspase-3 activity was positively correlated with MDA while negatively correlated with GSH, GSPx and GR in rat livers treated with AFB1. The apoptotic rate was significantly reduced when MEL co-administrated with AFB1. In rats which received MEL with AFB1, the levels of MDA and NO in liver tissues were significantly reduced while GSH and Zn levels and GSPx, GR and GST activities were significantly increased compared to AFB1 group. When MEL-MC co-administrated with AFB1 appeared more effective in reduction of apoptotic rate as detected by decline of caspase-3 activities (inhibition 66.82%) and confirmed by histopathology. CONCLUSION: AFB1 can lead to direct or indirect caspase-3 activation and consequently to apoptosis in rat liver. MEL treatment of rats could enhance hepatic antioxidant/detoxification system which consequently reduce the apoptotic rate and the necrobiotic changes in the liver. MEL-MC exhibited an efficient protective effect against AFB1. Thus, clinical application of MEL as therapy should be considered in cases of aflatoxicosis.

Aflatoxin B1↗
PubMed1982

Effect of beta-naphthoflavone on calf liver metabolism of aflatoxin B1.

Eight male Holstein calves were raised to 6 wk of age on whole milk at 8% of body weight and calf starter ration (15% crude protein) free choice. For each of 2 days prior to sacrifice, four of the calves were selected at random and administered the mixed function oxidase inducer beta-napthoflavone by bolus in starch carrier at .005% of metabolic body weight. After sacrifice, 10,000 X g postmitochondrial supernatant preparations were made from the excised livers and incubated with a 50-micrograms challenge of aflatoxin B1. Although there was no significant difference in total percent of the challenge metabolized, there was a large increase in aflatoxin M1 production by liver preparations from calves administered the flavone inducer. If the flavone family of inducers could alter the metabolic profile for aflatoxin in the adult lactating bovine, aflatoxin M1 excretion rates could be increased and pathways for production of mutagenic metabolites could be enhanced.

Aflatoxin B1↗
PubMed1995

Inhibition of CYP1A2 and CYP3A4 by oltipraz results in reduction of aflatoxin B1 metabolism in human hepatocytes in primary culture.

Dithiolethiones are thought to act as potent chemoprotective agents against aflatoxin B1 (AFB1)-induced hepatocarcinogenesis in the rat by inducing glutathione S-transferases (GSTs). To determine whether these antioxidants can be similarly effective in human beings, we have investigated metabolism of AFB1, in primary human hepatocytes with or without pretreatment by oltipraz (OPZ), a synthetic derivative of the natural 1,2-dithiole-3-thione. Aflatoxin M1 (AFM1), glutathione conjugates of AFB1 oxides (AFBSGs), and unchanged AFB1 were quantitated in cultures derived from eight human liver donors. Parenchymal cells obtained from the three GST M1-positive livers metabolized AFB1 to AFM1 and to AFBSGs derived from the isomeric exo-and endo-8,9-oxides, whereas no AFBSGs were formed in the GST M1-null cells. Pretreatment of the cells with 3-methylcholanthrene or rifampicin, inducers of CYP1A2 and CYP3A4, respectively, caused a significant increase in AFB1 metabolism. Although OPZ induced GST A2, and to a lesser extent GST A1 and GST M1, it decreased formation of AFM1 and AFBSG, which involves CYP1A2 and CYP3A4. Inhibition by OPZ of AFB1 metabolism by reducing CYP1A2 and CYP3A4 was also demonstrated by decreased activity of their monooxygenase activities toward ethoxyresorufin and nifedipine, respectively. The significant inhibition by OPZ of human recombinant yeast CYP1A2 and CYP3A4 was also shown. These results demonstrate that AFBSG can be formed by GST M1-positive human hepatocytes only, and suggest that chemoprotection with OPZ is due to an inhibition of activation of AFB1, in addition to a GST-dependent inactivation of the carcinogenic exo-epoxide.

Aflatoxin B1↗
PubMed1975

Influence of riboflavin on disturbances in trytophan metabolism and hepatoma production after a single dose of aflatoxin B1.

Female Wistar rats were given a single oral dose of aflatoxin B1, either alone or with a large amount of riboflavin. Biochemical and histologic studies were performed for 30 months. Nine animals of 19 in the aflatoxin-treated group and only 5 of 18 in the riboflavin-aflatoxin-treated group developed hepatomas. The number of rats was insufficient for tests of statistical significance to be fruitful. Urinary excretion of tryptophan metabolites was studied in aflatoxin- and riboflavin-treated rats after an oral administration of 10 mg tryptophan/100 g rat. Riboflavin did not affect the percentage of aflatoxin-treated animals with abnormal urinary excretion patterns, but did increase the magnitude of the disturbances in elimination of kynurenic and xanthurenic acids. The hepatic tryptophan-oxygenase activity was increased only in the two groups given riboflavin, and the levels of nucleic acids were the same in all groups.

Aflatoxins↗