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PubMed1991

Pharmacokinetics of intratracheally administered aflatoxin B1.

High concentrations of the carcinogen aflatoxin B1 (AFB1) are commonly found in respirable, airborne grain dusts, and inhaled AFB1 has been shown to be a risk factor for occupational pulmonary carcinogenesis. The fate of AFB1 exposure via the respiratory tract is therefore of interest in an evaluation of potential occupational risk. The pharmacokinetic disposition of intratracheally administered AFB1 was studied in male Sprague-Dawley rats. Blood and tissues were sampled at selected intervals for 3 weeks following administration of a single dose of grain dust-adsorbed or microcrystalline [3H]AFB1 (6 micro-Ci: microgramsg/kg). The blood concentration-time profiles from both groups best approximated a two-compartment open model with first-order absorption. The first-order absorption rate constant was significantly less in the animals given dust-adsorbed AFB1 than in those receiving microcrystalline AFB1 (0.083 vs -0.1060 min -1, respectively), although the first-order elimination rate constants for both groups were nearly identical (0.00928 and 0.00921 hr-1, respectively). Blood concentrations of the AFB1 metabolites AFM1, AFQ1, AFL, and AFP1 showed little differences among the two groups. The tissue concentrations of aflatoxins for the microcrystalline group were significantly greater at 3 hr in all tissues examined except for the trachea and lung in which those for the dust-adsorbed group were greater. At 3 days and 3 weeks, no significant differences between exposure groups were seen in any tissue except fat, where the amount of aflatoxins was greater for the dust-adsorbed group. AFB1 binding to DNA was significantly greater in the trachea and lung of the dust-adsorbed group compared to that in the microcrystalline group at 3 hr, whereas in the liver the AFB1-DNA binding in the microcrystalline group was significantly greater during this time. Thus, particle association of AFB1 increased the respiratory tract retention of this compound at early time intervals, which might be a factor in the reputed carcinogenic action of this compound in the respiratory tract. These findings may be useful as part of a comprehensive study to evaluate the disposition of AFB1 in individuals exposed to grain dusts laden with this carcinogen.

Absorption↗

PubMed1990

Aflatoxin production in cultures of Aspergillus flavus incubated in atmospheres containing selected cotton leaf-derived volatiles.

Aspergillus flavus, in solid culture, was exposed to individual selected, commercially obtained volatile compounds that were similar to volatile cotton leaf-derived components. The radial growth pattern of A. flavus and the production of aflatoxin were determined on these volatile exposed cultures. The most bioactive compounds C6-C9 alkenals, completely inhibited the growth of the fungus. Unexpected results demonstrated that 3-methyl-1-butanol and 3-methyl-2-butanol inhibited A. flavus growth by 20% but increased production of aflatoxin B1 by 1.5 to 2-fold. Other relationships of growth and aflatoxin production resulting from exposure to the bioactive volatiles are discussed.

Aflatoxin B1↗

PubMed1985

Characterization of water-soluble glucuronide and sulphate conjugates of aflatoxin B1. 2. Studies in primary cultures of rat hepatocytes.

Aflatoxin B1 and some of its metabolites were released from water-soluble aflatoxin conjugates isolated from rat primary hepatocyte cultures and hydrolysed by enzymes (beta-glucuronidase and sulphatase), by acid or by a combination of both treatments. The presence of AFB1 in the hydrolysates was detected on TLC plates, or indicated indirectly by the Ames mutagenicity assay. The aflatoxin conjugates were not mutagenic to Salmonella typhimurium strain TA98 in the presence of rat-liver S-9 mix. However, following enzymatic hydrolysis, the chloroform extract of the hydrolysate was highly mutagenic to the bacteria, indicating the presence of mutagenic AFB1. The conjugates AFB1-glucuronide and AFB1-sulphate are therefore produced from AFB1 in primary cultures of rat hepatocytes.

Aflatoxin B1↗

PubMed1983

Metabolic activation and bacterial mutagenicity of aflatoxin B1 in two different test systems.

The metabolism of aflatoxin B1 (AFB1) by liver post-mitochondrial supernatant fraction from phenobarbitone treated male albino rats in liquid suspension and soft-agar plate incorporation bacterial mutation assay systems has been studied. The AFB1 concentration used was in the range of those added to bacterial mutagenicity tests with this mycotoxin. Three oxidative metabolites of AFB1 viz the Tris derivative of AFB1 8,9-diol (derived from the 8,9-epoxide), aflatoxin Q1 (AFQ1) and M1 (AFM1) were observed. The metabolite profile and time course of formation were qualitatively similar in both assay systems. The rate and overall formation of metabolites in the soft-agar system was approximately one half that in the liquid suspension system which was reflected in decreased AFB1 induced bacterial mutation in the former system. The AFB1 metabolite profile in these in vitro systems did not mirror completely the reported in vivo profile seen in the rat, as aflatoxin P1 (AFP1) and a glutathione conjugate were not detected. No evidence was found for a prolongation of metabolism in the soft-agar system.

Aflatoxin B1↗

PubMed1990

Glucose alters rat liver S9-mediated mutagenesis, metabolism and DNA-binding of aflatoxin B1.

The administration of 30% glucose in drinking water to rats for 48 h caused a significant increase in the hepatic S9-mediated mutagenicity of aflatoxin B1, in Salmonella typhimurium TA100 and in the binding of alfatoxin B1, to calf thymus DNA in vitro. These effects correlated with a reduction in the metabolism and detoxification of aflatoxin B1, by S9 from glucose-treated rats and suggest that the oral intake of sugar may affect the hepatocarcinogenicity of aflatoxin B1.

Administration, Oral↗

PubMed1982

Aflatoxins, B1, B2, G1, G2 in primary liver cell carcinoma.

Aflatoxin B1, B2, G1, G2 levels were determined in sera of 20 patients with primary liver cell carcinoma (CC). Values of B1 above 0.15 microgram/ml were obtained in sera of three patients. Hepatitis B surface antigen (HBsAg) was detected in only 35% of patients. 50-90% of serum levels were cleared in 24 h in three patients studied. Although it is inconclusive as to the carcinogenic potential of aflatoxins in adult man, foodstuffs should be protected from excessive aflatoxin contamination.

Adult↗

PubMed1985

In vitro effect of aflatoxin B1 on rat liver macrophages (Kuffer cells).

The effect of aflatoxin B1 on the uptake and incorporation of [3H]leucine and [3H]uridine and on phagocytosis of latex particles was studied using cultures of rat liver macrophages (Kuffer cells). Aflatoxin B1 inhibited the incorporation of both isotopes, but inhibition of uridine incorporation was greater than that of leucine, suggesting that RNA synthesis was a major site of inhibition. Aflatoxin B1 also inhibited phagocytosis of latex particles in a time- and dose-dependent manner.

Aflatoxin B1↗

PubMed1982

Effect of cyclopropenoid fatty acids on the hepatic microsomal mixed-function-oxidase system and aflatoxin metabolism in rabbits.

Male New Zealand weanling rabbits were fed a diet containing 0.25% cyclopropenoid fatty acids for 28 days. Compared with the controls, the rabbits given cyclopropenoid fatty acids showed retarded growth, some moderate liver histological damage, altered hepatic mixed-function-oxidase activities and minor variations in vitro [14C]aflatoxin B1 metabolism. In in vitro assays the major hepatic metabolite of aflatoxin B1 (AFB1) was aflatoxicol (AFL) and the major AFL metabolite was AFB1. Minor amounts of aflatoxin M1 and a metabolite believed to be AFL-M1 were formed. The similarity of this AFB1 metabolite pattern to that in rainbow trout, taken together with the apparent absence of AFB1 detoxification products is consistent with the sensitivity of both species to the acute effects of AFB1.

Aflatoxin B1↗

PubMed1989

Purification and characterization of a hepatic mitochondrial cytochrome P-450 active in aflatoxin B1 metabolism.

We have previously shown that phenobarbital (PB) increases hepatic mitochondrial cytochrome P-450 (P-450) content and also the ability to metabolize hepatocarcinogen, aflatoxin B1 [Niranjan, B. G., Wilson, N. M., Jefcoate, C. R., & Avadhani, N. G. (1984) J. Biol. Chem. 259, 12495-12501]. In the present study, we have purified a mitochondrial-specific P-450 with an apparent molecular mass of 52 kdaltons (termed P-450mt3) from PB-induced rat liver using a combination of hydrophobic and ion exchange column chromatography procedures. Polyclonal antibody to P-450mt3 failed to cross-react with P-450mt1 and P-450mt2 purified from beta-naphthoflavone- (BNF) induced rat liver mitochondria. Furthermore, P-450mt3 shows an N-terminal amino acid sequence (Ala-Ile-Pro-Ala-Ala-Leu-Arg-Thr-Asp) different from those of both P-450mt1 and P-450mt2, as well as microsomal P-450b. The polyclonal antibody to P-450mt3 cross-reacted with a P-450 of comparable size purified from uninduced mitochondria. These two isoforms, however, showed difference with respect to catalytic properties and amino acid composition. In vitro reconstitution experiments show that P-450mt3 can actively metabolize diverse substrates including (dimethylamino)antipyrine, benzphetamine, and aflatoxin B1 but shows a low vitamin D3 25-hydroxylase activity. The mitochondrial P-450 from uninduced livers, on the other hand, shows relatively high [229 pmol min-1 (nmol of P-450)-1] vitamin D3 25-hydroxylase activity but a considerably lower ability for aflatoxin B1 metabolism and no detectable activity for (dimethylamino)antipyrine and benzphetamine metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)

Aflatoxin B1↗

PubMed1980

Carcinogen aflatoxin B1 is located preferentially in internucleosomal deoxyribonucleic acid following exposure in vivo in rainbow trout.

The purpose of this work was to investigate the distribution in chromatin of deoxyribonucleic acid (DNA) adducts of aflatoxin B1, following exposure in vivo. Rainbow trout were injected intraperitoneally with radiolabeled aflatoxin B1, a potent procarcinogen known to readily induced hepatocellular carcinomas in these fish. After maximum incorporation, liver nuclei were prepared and digested with micrococcal nuclease. Mono-, di-, and trinucleosomal fractions were purified from several stages of nuclease digestion, and the lengths and specific activities of their DNA were determined. The results indicate that aflatoxin B1 is approximately 5 times as likely on a per nucleotide basis to localize on internucleosomal (linker) DNA as on nucleosomal core DNA in this system.

Aflatoxin B1↗

PubMed1991

The isolation and culture of DHBV-infected embryo and duckling hepatocytes and the effect of aflatoxin B1 or irradiation on these cells.

The preparation of primary cultures of control and DHBV-infected duck hepatocytes from embryos and young ducklings is described. Cultures of both embryo and duckling hepatocytes secreted duck serum proteins. Cultures of hepatocytes established from ducklings maintained initial morphology for up to 3 weeks in culture and also exhibited high levels of metabolism of aflatoxin B1. Embryonic cell cultures rapidly lost ability to metabolise AFB1 and became overgrown by spindle-shaped cells. Both embryo and duckling cell cultures secreted infective DHBV, and had intracellular replicative forms of the virus. No integration of the virus into the duck genome was observed, and attempts to induce viral integration in the duckling hepatocytes using irradiation and aflatoxin B1 toxicity were unsuccessful. The results of the study lend further support to the suggestion that the rarity of liver cancer in DHBV-infected experimental ducks is related to an innate resistance of the hepatocytes to develop DHBV-DNA integration. Another possibility may be related to the lower oncogenic potential of the DHBV strain used for the study. However DHBV infected duckling hepatocytes would appear to offer a suitable material for studying viral replication and mechanisms of aflatoxin B1 toxicity during prolonged cell culture.

Aflatoxin B1↗

PubMed1989

Evidence for cytochrome P-450NF, the nifedipine oxidase, being the principal enzyme involved in the bioactivation of aflatoxins in human liver.

In vitro studies with human liver indicate that the major catalyst involved in the bioactivation of the hepato-carcinogen aflatoxin B1 (AFB1) to its genotoxic 2,3-epoxide derivative is cytochrome P-450NF (P-450NF), a previously characterized protein that also catalyzes the oxidation of nifedipine and other dihydropyridines, quinidine, macrolide antibiotics, various steroids, and other compounds. Evidence was obtained using activation of AFB1 as monitored by umuC gene expression response in Salmonella typhimurium TA1535/pSK1002 and enzyme reconstitution, immunochemical inhibition, correlation of response with levels of P-450NF and nifedipine oxidase activity in different liver samples, stimulation of activity by 7,8-benzoflavone, and inhibition of activity by troleandomycin. Similar results were obtained when levels of 2,3-dihydro-2-(N7-guanyl)-3-hydroxyaflatoxin B1 formed in DNA were measured. P-450NF or a closely related protein also appears to be the major catalyst involved in the activation of aflatoxin G1 and sterigmatocystin, the latter compound being more genotoxic than AFB1 in these systems. Several drugs and conditions are known to influence the levels and activity of P-450NF in human liver, and the activity of the enzyme can be estimated by noninvasive assays. These findings provide a test system for the hypothesis that a specific human disease state (liver cancer) is linked to the level of oxidative metabolism in populations in which aflatoxin ingestion is high.

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↗

PubMed1990

Characterization of c-Ki-ras and N-ras oncogenes in aflatoxin B1-induced rat liver tumors.

c-Ki-ras and N-ras oncogenes have been characterized in aflatoxin B1-induced hepatocellular carcinomas. Detection of different protooncogene and oncogene sequences and estimation of their frequency distribution were accomplished by polymerase chain reaction, cloning, and plaque screening methods. Two c-Ki-ras oncogene sequences were identified in DNA from liver tumors that contained nucleotide changes absent in DNA from livers of untreated control rats. Sequence changes involving G.C to T.A or G.C to A.T nucleotide substitutions in codon 12 were scored in three of eight tumor-bearing animals. Distributions of c-Ki-ras sequences in tumors and normal liver DNA indicated that the observed nucleotide changes were consistent with those expected to result from direct mutagenesis of the germ-line protooncogene by aflatoxin B1. N-ras oncogene sequences were identified in DNA from two of eight tumors. Three N-ras gene regions were identified, one of which was shown to be associated with an oncogene containing a putative activating amino acid residing at codon 13. All three N-ras sequences, including the region detected in N-ras oncogenes, were present at similar frequencies in DNA samples from control livers as well as liver tumors. The presence of a potential germ-line oncogene may be related to the sensitivity of the Fischer rat strain to liver carcinogenesis by aflatoxin B1 and other chemical carcinogens.

Aflatoxin B1↗

PubMedDate not supplied

Aflatoxin and Reye's syndrome: a study of livers from deceased cases.

In order to reinvestigate a strong reported association, we attempted to identify aflatoxin in the livers of 12 children who presumably died of Reye's Syndrome and in the liver of one child who died accidentally. Aflatoxins were detected, but not confirmed in only one of the liver specimens (limits of detection 20 ppt). In addition, the microscopic appearance of the livers was reviewed. Although most of the cases fit the clinical definition of Reye's Syndrome, the microscopic appearance of the liver was varied. We conclude that aflatoxin is not regularly recoverable from cases of Reye's Syndrome at a high rate, and question the proposed etiologic relationship. We confirm the varied appearance of the liver late in the course of Reye's Syndrome; however, microvesicular fat was present in most cases.

Aflatoxins↗

PubMed1983

Vitamin A and aflatoxin: effect on liver and colon cancer.

A vitamin A (retinyl acetate)-deficient diet enhanced liver cancer in rats exposed to aflatoxin B1 (AFB1) and also caused a 29% incidence of colon cancer. The following factors were considered in attempts to define conditions under which vitamin-A-deprived rats were more susceptible to colon cancer induced by AFB1: liver morphology, enterohepatic recirculation, level of reduced glutathione (GSH) in liver, and differing capacities for conjugation of aflatoxin to GSH. Enzyme concentrations in liver, in intestinal and colon mucosa, and in intestinal and colon contents suggested that AFB1 may have different metabolites and that there may be differing susceptibilities of colon mucosa to carcinogenesis. Binding studies supported this hypothesis. Previous studies have shown that colon epithelium from vitamin-A-deficient rats binds more AFB1 than colon epithelium from normal, vitamin-A-supplemented animals. In the present study, vitamin A supplementation to the vitamin-A-deficient rats before oral administration of 3H-AFB1 significantly decreased the binding capacity at 12 and 15 hours after dosing with the carcinogen. These results suggest that the effect of vitamin A on the metabolism of the carcinogen, particularly on binding of AFB1 to cellular macromolecules, may be the mechanism by which vitamin A modifies aflatoxin's carcinogenic potential, influenced in part through enzymatic mechanisms.

Aflatoxin B1↗

PubMed2004

Efficiency of different extraction solvent mixtures used in analyses of aflatoxins from a certified peanut meal reference material.

Four analytical methods with different extraction solvent mixtures were used to compare the efficiency of the extraction step in the analysis of aflatoxins from a reference material with a certified value of 206 +/- 13 microg aflatoxin B(1) kg(-1). The extraction mixtures used were chloroform-water (100 + 10), acetonitrile-water (60 + 40), acetone-water (85 + 15) and methanol-water (80 + 20). The analytical values determined from the extraction mixtures after correction for recovery were 211, 204, 163 and 120 microg kg(-1), respectively. The small amounts of aflatoxin B(2) in the reference material followed the same pattern. The selection of extraction solvent mixture is very important for achieving the true value and that correction for recovery does not always fully compensate for getting the correct analytical value.

Acetone↗

PubMed2005

Immunoaffinity clean-up and direct fluorescence measurement of aflatoxins B1 and M1 in pig liver: comparison with high-performance liquid chromatography determination.

An improved analytical method for aflatoxin B1 (AFB1) and aflatoxin M1 (AFM1) determination in pig liver is described, using an aqueous methanol extraction, an immunoaffinity column clean-up step and a direct fluorometric measurement for toxin detection and quantification. A detection limit of 1.0 microg kg-1 was achieved for AFB1 and AFM1. Mean recoveries of 80.7+/-9.0% for AFB1 spiked at 1.0-9.7 microg kg-1 levels and of 76.7+/-6.6% for AFM1 spiked at 1.0-5.5 microg kg-1 levels were obtained. Recovery data for spiked samples were statistically compared with those obtained by the same extract using classical reversed-phase high-performance liquid chromatography (RP-HPLC) with fluorescence detection, showing a significant correlation (p<or=0.05) for both aflatoxins. Both procedures were applied to the analysis of 50 pig livers, collected from 10 farms in the north of Italy. All the samples showed a contamination level lower than 1.0 microg kg-1 for AFB1 and one liver sample has shown an AFM1 contamination greater than 1.0 microg kg-1. The direct fluorometric procedure is particularly suitable for food manufacturers and control laboratories where quick procedures are mainly required for food quality control as well as for diagnostic and research purposes.

Aflatoxin B1↗