Aflatoxin Metabolism Research Articles

Uptake and metabolism of aflatoxin by Zea mays.

Uptake and metabolism of aflatoxin by Zea mays.

Effects of Dietary Aflatoxin on Performance and Zinc Metabolism in Dairy Calves

Young dairy calves were fed diets containing 40 or 640ppm zinc with 0 or 5ppm aflatoxin for 3 wk. The aflatoxin mixture contained 80.5% B1, 19.5% G1, and less than .1% B2 and G2. The aflatoxin fed calves exhibited characteristics signs of aflatoxicosis which included reduced feed intake, weight gains, nitrogen balance, pulse rate, and respiration rate, Feed intake and weight gains recovered some during the 3rd wk. No gross abnormalities were observed in the liver or other organs at autopsy. Addition of 600ppm zinc to diets containing aflatoxin did not alleviate the toxic conditions.Effects of aflatoxin or zinc metabolism were investigated during the 3rd week of treatment through oral dosing of zinc-65. Absorption of zinc-65 was slightly lower in aflatoxin-fed calve. However, the aflatoxin effect on absorption of zinc-65 was less than that of high dietary zinc. Retention of zinc-65 in small intestinal tissue was increased in aflatoxin-fed calves, but concentrations in other tissues were not affected. Stable zinc was reduced in liver and increased in kidney and three sections of the small intestine. Further research is needed to define more clearly the relationship of zinc to aflatoxin in dairy calves.

A comparative study on the biliary excretion of aflatoxin B 1 in the Albino rat ( Rattus norvegicus) and the African giant rat ( Cricetomys gambianus, Waterhouse)

1. Some comparative aspects of the metabolism of aflatoxin B 1 (AFB 1) have been investigated in 2 mammalian species. Albino rat ( Rattus sp.) and the African giant rat ( Cricetomys gambianus, Waterhouse). 2. Since the latter is being used for the first time in biochemical studies, its biology and domestication is briefly annotated. 3. The urine, bile and faeces of the rats initially injected with AFB 1 (1 mg/kg body weight) were assayed for metabolites of AFB 1. 4. These mammalian species demonstrate substantial difference in their metabolism of AFB 1 in vivo. 5. The role of aflatoxins as possible carcinogens in the African giant rat is discussed.

Effects of inducers and inhibitors on the metabolism of aflatoxin B, by rat and mouse

The microsomal metabolism of aflatoxin B 1 (AFB 1) via various pathways and the induction and inhibition specificities of these pathways were examined in Sprague-Dawley rats, inbred strains of mice, and recombinant inbred lines derived from AKR/J and C57L/J cross. The data suggests that the metabolism of aflatoxin B 1 is catalyzed by at least three different enzymes of the microsomal mixed function oxygenase system: one that mediates conversion to aflatoxin M 1 (AFM 1-hydroxylase) is cytochrome P-448-linked and is associated with the Ah locus at the level of regulatory genetic factors: the other two enzymes which are cytochrome P-450-linked, mediate the metabolism of aflatoxin B 1 to aflatoxin Q 1 (AFQ 1-hydroxylase) and to AFB 1-2,3-oxide (metabolic activation). Although AFQ 1-hydroxylase and metabolic activation, measured in vitro as the formation of DNA-alkylating metabolite( s), are not clearly distinguishable on the basis of induction and inhibition responses, the two activities can be distinguished on the basis of their kinetic parameters and genetic regulation: (a) the apparent K m of the metabolic activation pathway is almost three orders of magnitude (19.7 × 10 −4 M) higher than that of AFQ 1-hydroxylase (0.7 × 10 −4), [B. D. Roebuck and G. N. Wogan, Cancer Res. 37, 1649 (1977)]; and (b) while both activities are induced by phenobarbital (PB) and depressed by 3-methylcholanthrene (3-MC), unlike the metabolic activation, differences in the 3-MC-induced depression of AFQ 1-hydroxylase activity were noted in Ah responsive and nonresponsive strains. Kinetic studies revealed that metabolic activation of AFB 1 is linear with the time of incubation up to 20 min, with up to 2 mg of microsomal protein in the incubation, and has a pH optimum of 7 to 7.4. While PB pretreatment, relative to control, enhanced the apparent V max 3-fold, 3-MC depressed it about 60 per cent; however, the apparent K m values of the three microsomal preparations were of the same order of magnitude (1.3 to 2 × 10 −3 M). Under the conditions of the incubation, the minimum number of binding sites in DNA was estimated to correspond to a resultant specific activity of 8–9 nmoles AFB 1-metabolite bound/μmole DNA-P.

Similarity of nuclear and microsomal cytochromes P-450 in the in vitro activation of aflatoxin B 1

The metabolism of the hepatocarcinogen aflatoxin B 1 (AFB 1) by rat liver nuclear and microsomal preparations was examined using covalent binding of AFB 1 to nucleic acids as an index of activation. Nuclear activation of AFB 1 was induced by treatment of rats with either phenobarbital or 3-methylcholanthrene. The nuclear enzymes catalyzed AFB 1 binding to endogenous nucleic acids (principally DNA) but the binding was considerably enhanced over a wide concentration range of AFB 1 (2–500 μM) by the addition of microsomal enzymes. Antibodies, prepared to microsomal cytochromes P-450, inhibited metabolism of both AFB 1 and the model substrate 7-ethoxycoumarin in microsomal and nuclear preparations; antigen-antibody specificity was observed with regard to induction of the animals used for preparation of the enzymes. Immunodiffusion studies also indicated that microsomal and nuclear cytochromes P-450 are similar. The AFB 1-dna adducts produced by nuclei and microsomes were identical as judged by high pressure liquid chromatography of hydrolysates.

Metabolism of aflatoxin B 1 in cultured mouse hepatocytes: Comparison with rat and effects of cyclohexene oxide and diethyl maleate

The metabolism of aflatoxin B 1 was studied in cultured hepatocytes from adult male mice. After a 10-hr incubation, 89% of the dose of [ 14C]aflatoxin B 1 was converted to aqueous metabolites, while 0.77% was covalently bound to cellular macromolecules. In contrast, it has been previously shown that hepatocytes cultured from the rat and incubated with aflatoxin B 1 form 57.2% aqueous metabolites and covalently bind 12.2% to cellular macromolecules. The nearly 16-fold greater covalent binding in rat hepatocytes correlates with the greater susceptibility of the rat to the hepatocarcinogenic effect of aflatoxin B 1. Diethyl maleate and cyclohexene oxide each was shown to significantly increase the amount of covalent binding in hepatocytes from both species. At 10 −3 m, diethyl maleate and cyclohexene oxide, respectively, produced 805 and 61% increase in covalent binding in mouse hepatocytes, suggesting that both diol formation and glutathione conjugation are important detoxification pathways for aflatoxin B 1. Both pathways are apparently more active in mouse hepatocytes than in rat hepatocytes.

Effect of ethanol administration on the metabolism of aflatoxin B 1

Liver slices from rats given oral doses of ethanol (0.37, 1.11, and 1.86 g/kg body wt) for 1, 5, 10, and 20 days biotransformed AFB 1 to aflatoxin M 1 and Q 1 (AFM 1, AFQ 1) and a few other unidentified metabolites. Total biotransformation of AFB 1 varied inversely with the dose and duration of ethanol intake. Comparative fluorescent intensities suggested that the AFM 1 pathway was favored while that of AFQ 1 was depressed by ethanol administration.

The formation of 2,3-dihydro-2,3-dihydroxy aflatoxin B 1 by the metabolism of aflatoxin B 1 in vitro by rat liver microsomes

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Some high-performance liquid-chromatographic studies of the metabolism of aflatoxins by rat liver microsomal preparations.

The metabolism of aflatoxin B1 in vitro was examined in rat liver microsomal preparations. 2. H.p.l.c. (high-performance liquid-chromatographic) systems were used. A silica column was used to separate non-polar metabolites. A system utilizing a reversed-phase column which separates both poar and non-polar metabolites was also developed. 3. The principal metabolites of aflatoxin B1 found were aflatoxin M1, aflatoxin Q1 and a compound which co-chromatographed with a degradation product of aflatoxin B1 2,3-dihydrodiol. 4. The time course of metabolism of aflatoxin B1 by microsomal preparations isolated from control and phenobarbitone-pretreated rats was examined. The rate and extent of metabolism was greater with microsomal preparations from the latter. The formation of aflatoxin Q1 was enhanced 4--5-fold by phenobarbitone pretreatment, whereas the production of aflatoxin M1 was only increased 1--2-fold. The formation of the degradation product of aflatoxin B1 2,3-dihydrodiol was increased 4--5-fold by the pretreatment with phenobarbitone. 5. The microsomal metabolism of aflatoxins M1, P1 and Q1 was examined. Aflatoxin M1 apparently underwent very limited microsomal metabolism to more polar compounds. Aflatoxin P1 was not metabolized. The situation with aflatoxin Q1 was complicated in that it was metabolized in the absence of NADPH to an unidentified metabolite. Aflatoxin B1 appeared as a metabolite of aflatoxin Q1 only when NADPH was present, and the formation of more polar metabolites was also then observed.

Effect of vitamin a deficiency and excess on aflatoxin metabolism in the rabbit

Effect of vitamin a deficiency and excess on aflatoxin metabolism in the rabbit

Effects of the epoxide hydrase inhibitor, 1,1,1-trichloropropane-2,3-oxide on the genetic activity of aflatoxin B 1 metabolites in in vitro activation test systems

The epoxide hydrase inhibitor 1,1,1,-trichloropropane-2,3-oxide (TCPO) was genetically active to cells of S. cerevisiae and conidia of N. crassa. This genetic activity could be eliminated or reduced to near spontaneous levels in the presence of the S-9 fraction of hamster liver homogenate. The addition of TCPO to an in vitro activation system containing aflatoxin B 1 resulted in an increase in the genetic activity of aflatoxin B 1, and this increase was dependent on the dose of TCPO. These results are discussed in relation to the possible metabolism of the promutagen aflatoxin B 1.

Aflatoxin metabolism and absence of cytochrome P-450 in rat colon tissue during vitamin A malnutrition.

Homogenized mucosal linings prepared from vitamin A adequate and deficient male rats were used in metabolic studies of aflatoxin B1 (AFB1). Cytochrome P-420 was identified in both groups which metabolized AFB1 to 4 metabolic products in vitro. The implications of this observation are discussed in relation to colon carcinoma.

Formula omitted][formula omitted] metabolism of aflatoxin B 1 by rat liver nuclei

Rat liver nuclei were used to study the metabolism of aflatoxin B 1 (AFB 1). Nuclei were found to metabolize AFB 1 to aflatoxins M 1(AFM 1), Q 1(AFQ 1), and P 1(AFP 1); the formation of AFP 1 was relatively negligible. AFM 1 was preferentially formed when rats were pretreated with 3-methylcholanthrene (MC), whereas phenobarbital (PB) pretreatment enhanced the formation of both AFM 1 and AFQ 1. PB pretreatment also resulted in increased binding of AFB 1 metabolites to DNA and to other macromolecules in the nucleus. Following PB and MC pretreatment, induction specificities of the nuclear metabolism of AFB 1 were similar to those of the microsomal metabolism.

Maintenance of cytochrome P-450 and metabolism of aflatoxin B 1 in primary hepatocyte cultures

The cytochrome P-450 content of primary hepatocyte cultures was maintained at levels close to those found in vivo by using a defined medium containing testosterone, thyroxine, hydrocortisone, estradiol, glucagon, insulin, linoleic acid and oleic acid. Using these cultures, [ 14C]aflatoxin B 1, a potent liver carcinogen, was metabolized primarily to water-soluble metabolites. In agreement with in vivo results, aflatoxin M 1 was the only nonpolar metabolite detected. In addition, a significant portion of radioactivity was covalently bound to cell constituents. These results suggest that primary hepatocyte cultures may be a good model of the liver for studying the metabolism and mechanism of action of toxic chemicals.

Induction of mixed function oxidases on oral administration of dieldrin

The administration of dieldrin (30 mg/kg body weight) caused an increase in the liver weight of rats. The metabolism of aflatoxins B 1 and G 1 by the microsomes obtained from the liver of dieldrin-treated animals was enhanced significantly as compared to the controls showing that dieldrin increased the activity of mixed function hydroxylases. Dieldrin caused an increase in the activity of liver microsomal NADPH oxidase and a decrease in the lipid peroxidation. Dieldrin brought about an increase in the phosphatidylcholine content of rat liver.

Metabolism of aflatoxin and other mycotoxins in relation to their toxicity and the accumulation of residues in animal tissues

Abstract

Presence of aflatoxin B 1 in human liver in the United States

A sample of human liver tissue obtained at biopsy for study of the in vitro metabolism of aflatoxin B 1 was found to contain the toxin, apparently environmentally ingested, to the extent of 520 ng/g of wet liver. No other metabolites were detected. Upon incubation of a portion of the liver homogenate with an NADPH-generating system, the amount of aflatoxin B 1 in the liver chloroform-extractable fraction was reduced to 250 ng/g, and another metabolite of higher polarity was observed, to the extent of 40 ng/g. The patient, a resident of the United States, was suffering from carcinoma of the rectum and liver.

Oxidative metabolism of aflatoxin B 1: observations on the formation of epoxide-glytathione conjugate

Oxidative metabolism of aflatoxin B 1: observations on the formation of epoxide-glytathione conjugate

Metabolism and acute toxicity of aflatoxin B 1 in rats

Female rats are more resistant to the acute oral toxicity of aflatoxin B 1 and have higher tissue levels of aflatoxin M 1, a fluorescent hydroxylated metabolite, than males. These differences are reduced by castration, as castrated animals of either sex are more resistant and have higher tissue levels than entire males and females. The toxicity of a single oral dose of aflatoxin B 1 appears to be inversely related to levels of aflatoxin M 1 in the tissues.

Metabolism of aflatoxin B 1 by the guinea-pig

Aflatoxin B 1 was given by ip injection to year-old female guinea-pigs and 6 hr later aflatoxin B 1 and its metabolites were recovered and isolated chromatographically. Approximately 14% of the administered toxin was represented by the isolated compounds. Aflatoxin B 1 and M 1 each accounted for approximately 3%, and the remaining 94% was a product that migrated with the solvent front in a chloroform-acetone thin-layer chromatograph. This major metabolite exhibited a blue-green fluorescence and absorbed at 270 nm in methanolic solution. The compound appeared stable, since it rechromatographed as a single entitiy.