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PubMed1981

Modulation of hepatic transcription and translation during early stages of aflatoxin B1 carcinogenesis.

Isolated rat hepatocytes have been used to study the transcription and translation processes at varied time intervals after administration of a single dose (6 mg/kg) of hepatocarcinogen aflatoxin B1 (AFB1). The effects of AFB1 during the first 24 h of drug treatment show a characteristic inhibition followed by periods of rapid recovery and also a hyperactive state when both heterogeneous nuclear RNA (HnRNA) transcription and cytoplasmic translation processes reach about 200% of control. Analysis of [3H]orotic acid pulse-labeled HnRNA and cytoplasmic polyadenylic acid(poly (A)) containing mRNA on sucrose gradients under conditions which prevent aggregation show a stepwise reduction in the total isotopic incorporation as well as in the size distribution during the first 9 h of AFB1 treatment. Between 9 and 24 h after AFB1 treatment, there is a recovery in the total incorporation as well as in the size of HnRNA and poly (A) containing mRNA. Analysis of translation products by a two-dimensional procedure shows loss of some high molecular weight products in AFB1-treated cells. At 24 h after AFB1 treatment (hyperactive stage) there is a total recovery of activity. Also, several new translation products not detected in the control hepatocytes are synthesized at this stage. The hyperactive stage might represent gene-derepression or reprogramming of gene expression.

Aflatoxin B1↗
PubMed1975

Sequential histological and histochemical study of the rat liver after single-dose aflatoxin B1 intoxication.

Rats were given a single dose of aflatoxin B1 lethal to 50% of the animals (7.20 mg/kg). Their livers were examined histochemically in correlation with sequential histological lesions. Early periportal liver cell necrosis and marked biliary cell proliferation were observed. Periportal cytoplasmic glycogen and RNA depletion occurred during this early period and subsequently extended to the whole lobule. The enzymes investigated decreased or disappeared in the periportal area; but alkaline phosphatase increased strikingly in the centrolobular area, whereas canalicular adenosinetriphosphatase completely disappeared throughout the liver lobule. The histochemical changes reverted to normal after cessation of the necrosis. Histochemical techniques were more sensitive in detecting the vulnerability of the periportal parenchyma to aflatoxin. After the necrosis, regenerative foci appeared. They showed a variable content in glycogen and RNA and were characteristically enzyme deficient. This reflects the immaturity of regenerating hepatocytes. These early foci subsequently disappeared and are thus considered irrelevant to hepatomagenesis.

Adenosine Triphosphatases↗
PubMed2006

Biological degradation of aflatoxin B1 by Rhodococcus erythropolis cultures.

Aflatoxin contamination of food and grain poses a serious economic and health problem worldwide, but particularly in Africa. Aflatoxin B(1) (AFB(1)) is extremely mutagenic, toxic and a potent carcinogen to both humans and livestock and chronic exposure to low levels of AFB(1) is a concern. In this study, the biodegradation of aflatoxin B(1) (AFB(1)) by Rhodococcus erythropolis was examined in liquid cultures using thin layer chromatography (TLC), high performance liquid chromatography (HPLC), electro spray mass spectrometry (ESMS) and liquid chromatography mass spectrometry (LCMS). AFB(1) was effectively degraded by extracellular extracts from R. erythropolis liquid cultures. Results indicated that the degradation is enzymatic and that the enzymes responsible for the degradation of AFB(1) are extracellular and constitutively produced. Furthermore, the biodegradation of AFB(1) when treated with R. erythropolis extracellular fraction coincided with a loss of mutagenicity, as evaluated by the Ames test for mutagenicity.

Aflatoxin B1↗
PubMed1989

Modifying role of dietary factors on the mutagenicity of aflatoxin B1: in vitro effect of sulphur-containing amino acids.

Sulphur-containing amino acids including some derivatives have been tested for their effectiveness in suppressing the mutagenic activity of aflatoxin B1 in Salmonella typhimurium strains provided with a rat liver activation system. Cysteine and N-acetylcysteine have been found to be most effective in the 2 strains tested (TA100 and TA98). Glutathione (oxidised and reduced forms) has shown partial activity, while cystine and methionine are found to be partially effective only in strain TA100. Inhibition of mutagenicity may be due to interaction of these substances with microsomal enzymes resulting in interference with the formation of ultimate mutagenic species.

Aflatoxin B1↗
PubMed1989

Modification of the mutagenicity of aflatoxin B1 and N-methyl-N'-nitro-N-nitrosoguanidine by certain phenolic compounds.

Five natural and two synthetic phenolic compounds were tested for their ability to suppress mutagenicity of aflatoxin B1 (AFB1) and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in Salmonella typhimurium tester strain TA100. Caffeic acid and eugenol were observed to inhibit mutagenicity of both the carcinogens, while chlorogenic acid was effective in the case of AFB1 alone and ellagic acid and butylated hydroxytoluene were found to be antimutagenic only for MNNG. These differential activities of the phenolic compounds appeared to be due to their different modes of action towards direct and indirect acting carcinogens.

Aflatoxin B1↗
PubMed1985

Effect of butylated hydroxytoluene pretreatment on the excretion, tissue distribution and DNA binding of [14C]aflatoxin B1 in the rat.

The effect of butylated hydroxytoluene (BHT) pretreatment (0.5% in the diet for 10 days) on the excretion, tissue distribution and DNA binding of orally administered [14C]aflatoxin B1 (AFB1) was determined in male Fischer F344 rats. The amount of radioactivity excreted in the urine and faeces by 24 hr was higher in BHT-treated rats than in controls. Treatment with BHT enhanced the excretion of water-soluble metabolites in the urine and in the large intestines plus faeces at the earlier sampling times. The amount of radioactivity bound to hepatic nuclear DNA was six times less in the BHT-pretreated rats than in controls 6 hr after administration of the isotope. The half-lives of [14C]DNA in the rat liver were 30 and 46 hr for control and BHT-pretreated rats, respectively. These results indicate that BHT pretreatment may protect the animal from the carcinogenic effects of AFB1 by enhancing the detoxification and excretion of the mycotoxin.

Aflatoxin B1↗
PubMed1993

Destruction of phagocytosis-suppressing activity of aflatoxin B1 by ozone.

The impact of ozone on the immunity-impairing activity of aflatoxin B1 (AFB1) was studied. Phagocytosis by rat peritoneal macrophages, which was found to be suppressed in the presence of AFB1, remained unimpaired when the applied AFB1 was pretreated with ozone (1.2 mg l-1) for 6 min at a flow rate of 40 ml min-1. Hence, application of ozone on AFB1-contaminated foodcrops seems to be a promising preventive measure against any adverse immunological disorder in consumers.

Aflatoxin B1↗
PubMed1988

Preliminary studies on toxic effects of cyclopiazonic acid alone and in combination with aflatoxin B1 in non-human primates.

Results of experimental studies on toxicity of cyclopiazonic acid (CPA), a mycotoxin isolated from Aspergillus flavus, and toxicity of this toxin in combination with aflatoxin B1 (AFB1) are reported. Experiments were conducted in 16 vervet monkeys of both sexes. One male monkey was given 1 mg/kg per day of CPA intragastrically and the dose was doubled every third day to eventually achieve 60 mg/kg per day. Two males and 3 female monkeys were fed 20 mg/kg per day of CPA and terminated after 60 and 120 days, respectively. Two monkeys received AFB1 0.1 mg/kg per day, 2 received the same dose of AFB1 and 20 mg/kg per day of CPA. Four monkeys of both sexes served as controls. Results of experiments showed low toxicity of CPA in non-human primates with mild pathological changes in hepatocyte rough endoplasmic reticulum, small vessels and myocardium. Combined treatment with CPA and AFB1 indicated lack of a synergistic cumulative effect of both toxins. Animals treated with AFB1 only developed more advanced liver lesions and died earlier than those which also received high doses of CPA.

Aflatoxin B1↗
PubMed1990

Evidence for involvement of multiple forms of cytochrome P-450 in aflatoxin B1 metabolism in human liver.

Liver cancer is a major cause of premature death in many areas of Africa and Asia and its incidence is strongly correlated with exposure to aflatoxin B1 (AFB1). Because AFB1 requires metabolic activation to achieve a biological response, there is a need for detailed knowledge of the mechanism of activation to assess individual risk. We have carried out an extensive study using a total of 19 human liver samples to determine the individual variability in the metabolism of the toxin to mutagenic or detoxification products and to identify the specific cytochrome P-450 forms involved in these processes. Metabolism to the toxic 8,9-epoxide or to products mutagenic in the Ames test was found to exhibit very large individual variation. The rates of metabolic activation were highly correlated with both the level of proteins of the P450IIIA gene family and with the total cytochrome P-450 content of the microsomes. In agreement with this, antibodies reacting with P450IIIA proteins were strong inhibitors of both the metabolism and mutagenicity in the majority of the samples. However, the inhibition varied between 50% and 100%. The expression of a protein in the P450IIC gene family also correlated with AFB1 metabolism and mutagenicity. This result therefore indicated the involvement of cytochromes other than P450IIIA in the activation of AFB1 by human liver microsomes. This hypothesis was strongly supported by the finding that antibodies to P450IA2 and P450IIA1 were also effective inhibitors of metabolism in many of the samples. These data demonstrate that, although P450IIIA probably plays an important role in AFB1 activation, several other cytochrome P-450 forms have the capacity to activate the toxin. Similar considerations apply to detoxifying metabolism to aflatoxin Q1 and aflatoxin M1. The levels of expression of many of the forms of cytochrome P-450 involved in AFB1 metabolism are known to be highly sensitive to environmental factors. This indicates that such factors will be an important determinant in individual susceptibility to the tumorigenic action of AFB1.

Aflatoxin B1↗
PubMed1978

Examination and evaluation of germination and protonemal development for Onoclea sensibilis fern spores treated with aflatoxin B1.

Experiments were designed to test the effects of aflatoxin B1 (AFB1) on germination and subsequent development of the gametophytes of the sensitive fern Onoclea sensibilis. AFB1 concentrations used were 0, 2.5, 5.0, 7.5, 10.0 and 12.5 muM. Preliminary studies indicated that, under all AFB1 concentrations tested, germination was maximum after 144 hrs. Additional studies revealed that during this time period protonemal growth was in the log phase. Percent germination was inhibited by increasing concentrations of AFB1; A 50% inhibition was noted at 12.5 muM. In addition, increasing concentrations of AFB1 caused a reduction in the total number of cells per protonema. Preliminary analysis indicated that this was caused by a reduction of the rate of cell production rather than total inhibition of cell division. A comparison of the dose-response curves for both of the above effects demonstrated that sensitivity to AFB1 starts at 2.5 muM. This may indicate that AFB1 is acting on a process common to both phenomena. The fern spore germination system could be a "simple" model system in which to study the site and mode of action of AFB1.

Aflatoxins↗
PubMed1993

In vitro cytochrome P450 monooxygenase and prostaglandin H-synthase mediated aflatoxin B1 biotransformation in guinea pig tissues: effects of beta-naphthoflavone treatment.

In the present study, we examined the effects of treating guinea pigs with beta-naphthoflavone (BNF) on aflatoxin B1 (AFB1) metabolism by microsomal cytochrome P450 monooxygenase (P450) and prostaglandin H synthase (PHS) in liver, lung and kidney tissues. After BNF treatment, microsomal 7-ethoxyresorufin O-deethylase activity was induced 13-, 25- and 11-fold in lung, kidney and liver, respectively, confirming that the BNF treatment protocol was effective at inducing monooxygenase activity. Treatment of guinea pigs with BNF did not change [3H]AFB1-DNA binding catalyzed by microsomal PHS or P450 in lung, kidney or liver. In contrast, AFM1 formation by P450 was significantly increased in microsomes from all three organs. The data indicate that BNF-inducible P450 isozymes of the P4501A class are responsible for the biotransformation of AFB1 to non-toxic metabolites. Guinea pig kidney microsomes could also catalyze NADPH-dependent formation of aflatoxicol (AFL), a metabolite usually produced by a cytosolic steroid dehydrogenase. Renal microsomal AFL formation was not altered by prior BNF treatment. The results in the present study suggest that BNF may alter the bioactivation of AFB1 in guinea pig tissues by inducing P450 activity, leading to the formation of less reactive metabolite.

Aflatoxin B1↗
PubMed1994

[Effect of aflatoxin B1 on monooxygenase activity in liver microsomes exposed to cytochrome P-450].

Effect of aflatoxin B1 (AFB1) on microsomal ethoxycumarindeethylase (ECDE) and amidopyrindemethylase (APDM) activities in liver of Wistar rats treated with inductors of different forms of cytochrome P-450 (P-450) 3-methylcholanthrene (3-MC) and phenobarbital (PB) were studied. AFB1 caused strong inhibition of ECDE activity, induced by 3-MC. 150 for AFB1 was equal 3.2 10-5. In the same time AFB1 did not effect on basal and PB induced ECDE and APDM activities. Participation of MC induced forms of cytochrome P-450 (P-448) in activation of AFB1 is supposed.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1988

Preparation and characterization of monoclonal antibodies against a form of hamster liver cytochrome P-450 highly specific to aflatoxin B1.

Monoclonal antibodies were prepared against a form of cytochrome P-450 (designated as cytochrome P-450-I) purified from 3-methylcholanthrene-treated hamster livers which is highly specific to aflatoxin B1. The cytochrome P-450-I was detected in ELISA and Western blots in liver microsomes from 3-methylcholanthrene-treated hamsters and also from non-treated and phenobarbital-treated hamsters in smaller amounts. However, none of the liver microsomes from 3-methylcholanthrene-treated rat, rabbit, guinea pig and Suncus murinus contained the cytochrome P-450-I. These results suggest that cytochrome P-450-I is specific to hamster and is induced mainly by 3-methylcholanthrene.

Aflatoxin B1↗
PubMed1987

Metabolism and DNA binding of aflatoxicol and aflatoxin B1 in vivo and in isolated hepatocytes from rainbow trout (Salmo gairdneri).

The purpose of this study was to compare the metabolism and DNA binding of aflatoxicol (AFL) with that of aflatoxin B1 (AFB1) in vivo and in isolated hepatocytes from Mt Shasta strain rainbow trout (Salmo gairdneri). Maximum total binding of [3H]AFL to liver DNA from trout exposed by intraperitoneal injection was 38-47% of that of [3H]AFB1 over a 1-7 day period. The average AFL/AFB1 DNA binding ratio in 1-h incubations with isolated hepatocytes was 0.67 +/- 0.36 (n = 13). In freshly isolated hepatocytes, substantial interconversion between AFB1 and AFL via reductase and dehydrogenase enzymes was observed. Total in vivo excretion of conjugates in bile over 4 days was greater for [3H]AFL substrate than for [3H]AFB1. To determine if AFL binding was due to direct activation or to prior metabolism to AFB1 followed by activation, AFL with a tritium atom on the carbon containing the cyclopentenol function [1-3H]AFL, was synthesized and incubated with hepatocytes. Binding of [1-3H]AFL was 3% that of [3H]AFB1 and represents only direct binding of the intact cyclopentenol epoxide molecule before transformation to AFB1 and consequent loss of 3H. H.p.l.c. analysis of DNA hydrolyzed after incubation with [1-3H]AFL resulted primarily in production of non-radioactive 8,9-dihydro-8-(N7-guanyl)-9-hydroxyaflatoxin B1 (AFB1-N7-guanine). A radioactive peak estimated to be 1% as abundant as the AFB1-N7-guanine was also observed. The overall binding of generally labeled [3H]AFL to trout liver DNA in vivo and in freshly prepared hepatocytes correlates well with available tumor incidence and mutagenicity data. Conclusions from these findings are that direct interaction of AFL-8,9-epoxide with DNA is of relatively minor quantitative importance in rainbow trout hepatocytes and that the major adduct results from conversion of AFL to AFB1 prior to epoxide formation.

Aflatoxin B1↗
PubMed1992

Enhanced hepatotoxicity of aflatoxin B1 in the rat by ethanol: ultrastructural changes.

The effect of ethanol pretreatment on aflatoxin B1 (AFB1)-induced ultrastructural alteration in hepatocytes was investigated in male Wistar rats. Pretreatment with 4 oral doses of ethanol (4.0 g/kg body wt. each) at 48, 45, 24 and 21 h prior to a single intraperitoneal administration of AFB1 (2.0 mg/kg body wt.) produced an alteration of fine structure more extensive than that observed after administration of AFB1 or ethanol alone. The organelles most affected were the mitochondria, endoplasmic reticulum and nucleus. The degree of nuclear edema, rough endoplasmic reticulum dilatation and mitochondrial swelling in hepatocytes from rats treated with ethanol and AFB1 was much greater than that of hepatocytes from rats treated with AFB1 or ethanol alone. Thus, ethanol may play a specific role in the potentiation of hepatic injury induced by AFB1 at the mitochondrial, endoplasmic reticular and nuclear level.

Adenosine Triphosphate↗
PubMed1989

Production of aflatoxin B1 by Aspergillus ruber THOM and CHURCH.

Production of aflatoxins by Aspergillus ruber THOM and CHURCH was first reported by KULIK and HOLADAY (1967), although these results have lacked confirmation. In this paper we provide evidence that this fungal strain produces aflatoxins. This finding has implications for food hygiene, especially in countries where such moulds are used in the preparation of foodstuffs.

Aflatoxin B1↗
PubMed1997

Aflatoxin B1 8,9-epoxide hydrolysis in the presence of rat and human epoxide hydrolase.

Aflatoxin B1 (AFB1) must be activated to the electrophilic AFB1 exo-8,9-epoxide to be genotoxic and carcinogenic. A role for epoxide hydrolase in detoxication has been suggested but never directly addressed. In light of recent studies determining the instability of AFB1 exo-8,9-epoxide in H2O, a role for epoxide hydrolase appears dubious. Rat liver or recombinant rat epoxide hydrolase provided an enhancement to the already fast hydrolysis rate of up to 22%. Purified human epoxide hydrolase provided no detectable enhancement to the rate of chemical hydrolysis. Some reduction in the genotoxicity of AFB1 was observed when the ratio of rat epoxide hydrolase to cytochrome P450 was high (approximately 50-fold). An 80-fold excess of human epoxide hydrolase over cytochrome P450 only produced an effect of approximately 25% inhibition. It appears, therefore, that there is little evidence to support a role for epoxide hydrolase in the detoxication of AFB1.

Aflatoxin B1↗
PubMed1986

Effect of purified rat and hamster hepatic glutathione S-transferases on the microsome mediated binding of aflatoxin B1 to DNA.

Rat and hamster liver cytosolic glutathione (GSH) S-transferases purified by GSH-affinity chromatography have been examined for their effects on the microsome mediated binding of aflatoxin B1 (AFB1) to DNA and on the conjugation of AFB1-2,3-epoxide with GSH. Like previous studies with cytosolic preparations (Raj et al. (1984) Carcinogenesis 5, 879), our present study with purified GSH S-transferases showed 2-3-fold more inhibitory activity of AFB1-DNA binding with hamster than that with the rat. Concomitant with the inhibition of AFB1-DNA binding, increase in AFB1-GSH conjugation occurred. Subunit compositions of GSH S-transferases indicate preponderance of Yb and Ya subunits in the hamster and rat, respectively. The role of GSH S-transferases in modulating AFB1-DNA binding and AFB1 induced hepatocarcinogenesis is discussed.

Aflatoxin B1↗