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PubMed1983

Identification and mutagenicity of aflatoxicol-M1 produced by metabolism of aflatoxin B1 and aflatoxicol by liver fractions from rainbow trout (Salmo gairdneri) fed beta-naphthoflavone.

beta-Naphthoflavone (beta NF) fed to rainbow trout (Salmo gairdneri) at 50 or 500 ppm in the diet, modified the in vitro metabolism of aflatoxin B1 (AFB1) by the postmitochondrial fraction (PMF) of the liver. Production of aflatoxicol (AFL) was significantly less in the 500 ppm beta NF-fed group (33.9 ng/mg protein) than in the control group (45.7 ng/mg protein), aflatoxin M1 production was dependent on the dose of beta NF, being greatest in the 500 ppm beta NF-fed group (48.9 ng/mg protein), intermediate in the 50 ppm beta NF-fed group (3.7 ng/mg protein), and was not detected in controls. A new trout metabolite, 4-hydroxyaflatoxicol (aflatoxicol M1, AFLM1) was also detected in small amounts from in vitro metabolism by liver PMF from beta NF-fed trout. Sufficient quantities of AFLM1 for confirmation of identity by ultraviolet spectra, mass spectra and nuclear magnetic resonance spectra were prepared by biotransformation of AFL using liver microsomes and isolation by HPLC. In a modified Ames mutagen assay with Salmonella typhimurium TA98, ALFM1 was 4.1% as mutagenic as AFB1 in a previous determination. The carcinogenicity of AFLM1 to rainbow trout is expected to be considerably less than that of AFB1.

Aflatoxin B1↗
PubMed1975

Studies on the recovery of aflatoxin b1 injected into frozen beef at different intervals of storage.

Beef stored at --18 degrees C for 20,25,32,153, and 183 days showed a diminution in the recovery of injected aflatoxin B1. An unusual passing of aflatoxin in ether and hexane fractions of silica gel column was noted. Ether fraction contained aflatoxin B1-like substance from stored beef samples. Probable occlusion of aflaton B1 to meat constituents due to physico-chemical changes associated with muscle during storage was discussed.

Aflatoxins↗
PubMed1987

Effect of (+)-catechin, dimethyl sulfoxide and ethanol on the microsome-mediated metabolism of two hepatocarcinogens, N-nitrosodimethylamine and aflatoxin B1.

Effects of catechin, a plant phenolic flavonoid, and of the commonly used organic solvents dimethyl sulfoxide (DMSO) and ethanol (EtOH) on the microsome-mediated metabolism of two hepatocarcinogens, N-nitrosodimethylamine (NDMA) and aflatoxin B1 (AFB1), are presented. Using hamster liver microsomes as a source of mixed-function oxidases, it was shown that catechin at 0.1-0.2 mM levels had no effect on the oxidation of either carcinogen. However, at 1-5 mM levels it caused a concentration-dependent inhibition (38-70%) of the formation of formaldehyde from NDMA, and at the 5 mM level it caused a 40% inhibition of AFB1-DNA binding. DMSO and EtOH totally inhibited NDMA demethylase activity but had little effect on the binding of AFB1 to DNA. These observations indicate that the mixed-function oxidases (cytochrome P450) essential for the metabolic activation of these carcinogens exhibit different sensitivities to different inhibitors.

Aflatoxin B1↗
PubMed1987

The direct mutagenicity of aflatoxin B1 and metabolites to Salmonella typhimurium: structure mutagenicity relationships and mechanisms of action.

The non-microsomal mutagenesis of a series of aflatoxins in Salmonella typhimurium TA100 and TA98 was evaluated. Aflatoxin B1 had the highest direct or non-microsomal potency. However, the order of direct mutagenic activity as compared to indirect or microsomal activity was as follows; aflatoxin Q1 much greater than G1 greater than B1 greater than aflatoxicol. This order was determined using a new plotting strategy for identification of direct contribution to the mutagenesis, an I-D graph (indirect vs. direct activities). It is suggested from our analyses that the fused carbonyl bearing rings in aflatoxins are necessary for direct mutagenesis. This activity is facilitated by oxygen substitution at the terminal carbonyl ring. On the other hand, the cyclopentene structure may either attenuate or amplify the microsome mediated mutagenesis which is assumed to be produced by the vinyl ether portion of the molecule. This was dependent upon substitution at the cyclopentene. Stereo-sensitivity was revealed by the greater mutagenicity of unnatural aflatoxicol over the natural epimer. These observations point to a need for further study of direct binding and transmolecular-structure-activity relationships in order to fully develop the mechanism of aflatoxin mutagenicity.

Aflatoxin B1↗
PubMed1991

Modulatory effect of crocetin on aflatoxin B1 cytotoxicity and DNA adduct formation in C3H10T1/2 fibroblast cell.

Crocetin is a carotenoid isolated from the seeds of Cape jasmine (Gardenia jasminoides). The cytotoxicity and DNA-adduct formation of rat microsome-activated aflatoxin B1 (AFB1) in the C3H10T1/2 cells were significantly inhibited by pretreatment of crocetin. Most significant inhibition was found at the time of 9 h after crocetin pretreatment. Under these experimental conditions, consistent elevation in the cytosolic glutathione (GSH) levels and the activities of GSH S-transferase (GST) and GSH-peroxidase (GSH-Px) were observed. Crocetin treatment also resulted in a decrease in AFB1-DNA adduct formation in vitro, while no effect of crocetin on the formation of AFB1-8,9-oxide in vitro system was detected as measured by the Trisdiol method. From these results, we suggested that the protective effect of crocetin on the AFB1-cytotoxicity in C3H10T1/2 cells might be due to the cellular defense mechanisms that elevated the cytosol GSH and the activities of GST and GSH-Px.

Aflatoxin B1↗
PubMed1991

Direct and microsomal activated aflatoxin B1 exposure and its effects on turkey peritoneal macrophage functions in vitro.

Sephadex-elicited turkey peritoneal exudate cells were used to establish adherent macrophage monolayers on glass coverslips in order to determine the effects of aflatoxin B1 (AFB1) on macrophages. Adherent macrophage monolayers were exposed to increasing doses of AFB1 (5, 10, 20, and 40 micrograms), either directly, or to 0.01, 0.1, 0.5, 1, and 5 micrograms of AFB1 in the presence of a chicken microsomal mixed function oxidase system (MFO). Cultures were incubated with the appropriate treatments for 1 hr, then washed and allowed to recover in fresh growth medium for 2 hr. Direct exposure of macrophages to AFB1 had no detrimental effect on macrophage adherence, percentage damaged, percentage phagocytic, and the number of antibody-coated or uncoated sheep red blood cells internalized per phagocytic macrophage when compared with the sham or solvent treated cultures. However, the addition of MFOs to the cultures treated with much lower doses of AFB1 resulted in significantly higher morphological alterations along with a reduction in cell adherence and phagocytic potential. Addition of piperonyl butoxide (a P450 inhibitor) abrogated AFB1-MFO induced alterations. Data collected in this study suggest that turkey macrophages are resistant to the direct exposure of AFB1 and that AFB1 induced alterations in macrophage effector functions are due to metabolic activation of AFB1 by MFOs.

Aflatoxin B1↗
PubMed1997

Mucosal unresponsiveness to aflatoxin B1 is not broken by cholera toxin.

Rabbits immunized via chronically isolated ileal loops with aflatoxin B1 (AFB) conjugated to porcine thyroglobulin (TG) mixed with the mucosal adjuvant cholera toxin (CT) produced very small mucosal antibody responses to AFB. Strong mucosal and systemic antibody responses to CT and TG were generated by this immunization protocol, suggesting that the observed unresponsiveness was specific to AFB. Parenteral immunization with AFB-TG produced strong serum IgG anti-AFB responses, indicating that the conjugate preparation was immunogenic and that the rabbits possess the requisite systemic B and T cell repertoires to recognize and respond to AFB. This mucosal unresponsiveness was distinct from oral tolerance, as animals immunized mucosally with AFB-TG mixed with CT produced vigorous serum IgG anti-AFB responses upon subsequent parenteral immunization with AFB-TG. In vitro mitogen stimulation of lymphocytes isolated from Peyer's patches and mesenteric lymph nodes of unimmunized rabbits revealed the presence of AFB-specific B cells at levels comparable with these found in the spleen. These observations indicate that unresponsiveness to AFB is hapten-specific, restricted to the mucosa, and refractory to the adjuvancy of CI.

Adjuvants, Immunologic↗
PubMed1996

Genotoxicity of aflatoxin B1: evidence for a recombination-mediated mechanism in Saccharomyces cerevisiae.

The potent liver carcinogen aflatoxin B1 (AFB1) is metabolized by cytochrome P450 to the mutagenic epoxide. We have observed that activated AFB1 also strongly induced mitotic recombination in the yeast Saccharomyces cerevisiae. To compare the recombinogenicity of AFB1 to its mutagenicity, three metabolically competent S. cerevisiae strains have been constructed. The frequencies of induced recombinants resulting from gene conversion or chromosomal translocations were determined by different prototrophic selections using two strains, whereas the inducibility of forward mutations was determined by the frequency of drug resistance in the third strain. Human cytochrome P4501A1- (CYP1A) and NADPH-cytochrome P450-oxidoreductase cDNAs were expressed in the strains to ensure intracellular metabolism to the epoxide. Exposure of the strains to AFB1 resulted in a 139- and 24-fold increase in the translocation and gene conversion frequencies, respectively, whereas the mutation frequency was increased only 3-fold. In contrast, benzo[a]pyrene-7,8-dihydrodiol and ethyl methanesulfonate induced mutation and mitotic recombination to similar degrees. We conclude that AFB1 exerted a strong recombinogenic, but only a weak mutagenic, effect. The recombinogenicity of AFB1 in yeast may indicate a mechanism for the high proportion of loss of heterozygosity that has been detected in AFB1-related human liver cancers.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1990

Rat liver endothelial and Kupffer cell-mediated mutagenicity of polycyclic aromatic hydrocarbons and aflatoxin B1.

The ability of isolated rat liver endothelial and Kupffer cells to activate benzo(a)pyrene (BP), trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene (DDBP), trans-1,2-dihydroxy-1,2-dihydrochrysene (DDCH), and aflatoxin B1 (AFB1) to mutagenic metabolites was assessed by means of a cell-mediated bacterial mutagenicity assay and compared with the ability of parenchymal cells to activate these compounds. Endothelial and Kupffer cells from untreated rats were able to activate AFB1 and DDBP; DDBP was activated even in the absence of an NADPH-generating system. Pretreating the animals with Aroclor 1254 strongly enhanced the mutagenicity of the dihydrodiol, whereas the mutagenicity of AFB1 showed a slight increase. BP and DDCH were only activated by endothelial and Kupffer cells isolated from Aroclor 1254-pretreated rats. Parenchymal cells from untreated animals activated all four carcinogens tested; Aroclor 1254 enhanced the parenchymal cell-mediated mutagenicity of BP and DDCH but did not affect that of DDBP and clearly reduced that of AFB1. The reduced mutagenicity of AFB1 correlates with the decrease in the amount of 2 alpha-hydroxytestosterone formed when testosterone was incubated with parenchymal cell microsomes from Aroclor 1254-pretreated rats (compared with microsomes from untreated animals): the formation of 2 alpha-hydroxytestosterone is specifically catalyzed by cytochrome P-450h, a hemoprotein thought to be involved in the activation of AFB1. These results show that not only rat liver parenchymal cells, but also endothelial and Kupffer cells, activate several carcinogens to mutagenic metabolites.

Aflatoxin B1↗
PubMed1995

Extrahepatic bioactivation of aflatoxin B1 in fetal, infant and adult rats.

Whole-body autoradiography of 3H-labelled aflatoxin B1 (3H-AFB1) in female non-pregnant adult and infant Sprague-Dawley rats showed retention of tissue-bound radioactivity, in addition to the liver, in the mucosa and some glands in the nose, and in the mucosa of the nasopharynx, trachea, bronchioles, colon and caecum. The extrahepatic binding was most pronounced in the infant rats. In a rat pretreated with the glutathione (GSH)-depleting agent phorone, bound labelling was also seen in the superficial part of the mucosa of the glandular stomach. Autoradiography of 3H-AFB1 in pregnant rats showed a marked localization of bound AFB1-metabolites in the fetal nasal olfactory and tracheal mucosa. In vitro experiments demonstrated that the nasal olfactory mucosa had a much higher capacity than the liver to form AFB1-metabolites which bound to DNA and protein. The bioactivation was observed both pre- and post-natally and increased with age. Bioactivation was found also in the caecum, the colon and the lateral nasal gland (Steno's gland), but not in the small intestine, oesophagus or Harderian gland. Our results indicated that glutathione-S transferase activity catalysing the AFB1-8,9-epoxide GSH-conjugation was present in the nasal olfactory mucosa and liver at all pre- and post-natal ages examined. Several of the extrahepatic tissues able to bioactivate AFB1 have been reported to be targets for the carcinogenicity of the substance. Our results indicate that the extrahepatic carcinogenicity of AFB1 is correlated to a local bioactivation in the sensitive tissues.

Aflatoxin B1↗
PubMed1990

Contribution of aflatoxin B1 and hepatitis B virus infection in the induction of liver tumors in ducks.

The study of two major risk factors in the development of hepatocellular carcinoma, namely persistent hepatitis virus infection and exposure to dietary aflatoxins, has been hampered by lack of an experimental system. To this end we have used a Pekin duck model to examine the effect of congenital duck hepatitis B virus (DHBV) infection and aflatoxin B1 (AFB1) exposure in the induction and development of liver cancer. AFB1 was administered to DHBV infected or noninfected ducks at two doses (0.08 and 0.02 mg/kg) by i.p. injection once a week from the third month posthatch until they were sacrificed (2.3 years later). Two control groups of ducks not treated with AFB1 (one of which was infected with DHBV) were observed for the same period. Each experimental group included 13-16 ducks. Higher mortality was observed in ducks infected with DHBV and treated with AFB1 compared to noninfected ducks treated with AFB1 and other control ducks. In the groups of noninfected ducks treated with high and low doses of AFB1, liver tumors developed in 3 of 10 and 2 of 10 ducks; in infected ducks treated with the high dose 3 of 6 liver tumors were observed and none in the low dose of AFB1. No liver tumors were observed in the two control groups. Ducks infected with DHBV and treated with AFB1 showed more pronounced periportal inflammatory changes, fibrosis, and focal necrosis compared to other groups. All DHBV carrier ducks showed persistent viremia throughout the observation period. An increase of viral DNA titers in livers and sera of AFB1 treated animals compared to infected controls was frequently observed. No DHBV DNA integration into the host genome was observed, although in one hepatocellular carcinoma from an AFB1 treated duck, an accumulation of viral multimer DNA forms was detected. The metabolism of AFB1 in infected and noninfected duck liver was also examined. The study on the role of DHBV infection and AFB1 in the etiopathogenesis of liver tumors may help to clarify some of the basic mechanisms of carcinogenesis.

Aflatoxin B1↗
PubMed1991

Effect of long term feeding and withdrawal of aflatoxin B1 and ochratoxin A on kidney cell transformation in albino rats.

Subacute doses (1/20 LD50) of aflatoxin B1 and ochratoxin A were fed to weanling albino rats individually and in combination for 36 weeks and then rats were maintained on toxin free normal diet for a period of 24 weeks. Livers of rats were fatty, wherever aflatoxin was administered but the enzyme activity did not show significant differences among various groups. However, in a few individuals whose livers were severely affected, higher concentrations of urine creatinine, liver RNA and DNA, and ALT enzyme activity were recorded. Histopathological examination showed various stages of hepatoma and hepatocarcinoma including nodular hyperplasia, hypertrophy, vacuolisation, degeneration, pseudolobulation, cellular infiltration and fibrosis of liver of rats fed with aflatoxin individually and in combination. Few anaplastic cells in the corticomedullary region and nuclear enlargement of proximal tubular epithelium of kidney were found wherever combined toxin and ochratoxin alone were administered. Liver tumor expression was time dependent.

Administration, Oral↗
PubMed1995

[Production and characterization of monoclonal antibody against aflatoxin B1].

Two hybridoma cell lines 1B5 and 2F1 capable of secreting specific monoclonal antibodies (McAbs) against aflatoxin B1 (AFT B1) were obtained. BALB/c mice were immunized by intrasplenic injection of AFT B1-human serum albumin conjugate (AFT B1-HSA) containing 9 AFT B1 residue per molecule. Spleen cells of BALB/c mouse with high serum antibody titer were fused with SP 2/0 myeloma cells in the presence of polyethylene glycol. Hybridoma cell lines were selected by using an indirect ELISA with AFT B1-keyhole limpet haemocyanin as coating antigen and grown as ascite tumour cells in BALB/c mice which previously had received an intraperitoneal injection with Freund's incomplete adjuvant. The McAbs were found to have strong reaction with AFT B1-bovine serum albumin conjugate (AFT B1-BSA) and no reaction with HSA or BSA. The reactivity of the McAbs with AFT analogs was determined by an indirect inhibition ELISA and the concentrations (ng/ml) required to inhibit 50 binding of McAb to AFT B1-BSA conjugate solid phase were AFT B1 4.0ng/ml, B2 36.9ng/ml, G1 23.3ng/ml and G2 403.3ng/ml for 1B5 McAb, and AFT B1 2.4ng/ml, B2 2.6ng/ml, G1 2.8ng/ml and G2 4.7ng/ml for 2F1 McAb.

Aflatoxin B1↗
PubMed1985

Covalent binding of aflatoxin B1 to liver DNA in rats pretreated with ethanol.

Male Fischer F-344 rats were given ethanol in the drinking water and/or by single oral administration. Following this, the animals received p.o. 100 ng/kg of the hepatocarcinogen [3H]aflatoxin B1 (AFB1). 24 h later, the level of DNA-bound AFB1 was determined in the liver and was found not to be affected by any type of ethanol pretreatment. A cocarcinogenic effect of ethanol in the liver is therefore unlikely to be due to an effect on the metabolic activation inactivation processes governing the formation of DNA-binding AFB1 metabolites.

Administration, Oral↗
PubMed1990

In vitro inhibition of dihydropyridine oxidation and aflatoxin B1 activation in human liver microsomes by naringenin and other flavonoids.

Recent in vivo studies in humans have shown a dramatic effect of grapefruit juice in blocking the oxidation of dihydropyridine calcium channel blockers. The flavonoid naringin is the most abundant natural product specific for grapefruit and related citrus--the aglycone naringenin, known to be readily formed from naringin in humans, was found to inhibit the oxidation of the dihydropyridines nifedipine and felodipine in human liver microsomal preparations. These observations were of interest in light of the knowledge that the same human liver cytochrome P450 (IIIA4) appears to be a major catalyst in both nifedipine oxidation and aflatoxin B1 activation. Several flavones inhibited the in vitro activation of aflatoxin B1 in a system employing umuC gene activation due to DNA damage in Salmonella typhimurium TA1535/pSK1002, with naringenin being as effective as any. The high concentration of derivatives of naringenin in certain citrus fruits may be of relevance to cancer chemoprevention involving those carcinogens that are activated by cytochrome P-450IIIA4.

Aflatoxins↗
PubMed1986

Protection of crocin dyes on the acute hepatic damage induced by aflatoxin B1 and dimethylnitrosamine in rats.

Chemopreventive agents are compounds that inhibit carcinogenesis when administered prior or subsequent to a course of carcinogen administration. The effects of dietary administration of crocin dyes on the hepatic damage induced by aflatoxin B1 (AFB1) and dimethylnitrosamine (DMN) in rats were investigated. Female Sprague-Dawley rats were treated with different dosages of AFB1 (0.9 or 4.5 mg/kg) or DMN (8 or 20 mg/kg) by i.p. administration, and the different degrees of hepatic damage were revealed by the elevations of levels of serum marker enzymes such as aspartate amino-transferase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transpeptidase and lactic dehydrogenase. Pre-treatment of the animals with crocin dyes 50 mg/kg daily for three consecutive days, the enzyme elevations were significantly suppressed. This suggested that the crocin dyes possessed chemopreventive effects on the early acute hepatic damage induced by AFB1 or DMN. Feeding experiments demonstrated that crocin dyes at 0.1% in the diet could suppress partially the chronic hepatic damage induced by multiple dosages of AFB1 or DMN, but at a higher concentration of 1% crocin dye failed to do so because of their host toxicity. Crocin dyes are extracted from the fruits of Gardenia jasminoides and consist of carotenoids and geniposides as active principles. The protective mechanisms of crocin dyes may be attributed to their carotenoids which are converted metabolically to retinoids in rats.

Aflatoxin B1↗
PubMed1985

Metabolism, covalent binding, and mutagenicity of aflatoxin B1 by liver extracts from rats of various ages.

The ability of S-9 fractions isolated from the livers of 4-, 12-, and 26-month-old male inbred F344 rats to activate and metabolize the hepatocarcinogen aflatoxin B1 [(AFB1) CAS: 1162-65-8] was studied. The following observations were made: The activation of AFB1 to compounds that are mutagenic in the Ames Salmonella-microsome test and to compounds that covalently bind DNA in vitro was similar for liver S-9 from 4- and 12-month-old rats. A 30-50% decrease in the activation of AFB1 occurred in rats between 12 and 26 months of age. The in vitro metabolism of AFB1 to chloroform-soluble and water-soluble metabolites was similar for 4- and 12-month-old rats and decreased significantly in rats after 12 months of age. The proportion of most of the chloroform-soluble metabolites of AFB1 formed by liver S-9 from 4-, 12-, and 26-month-old rats was similar. However, the proportion of aflatoxicol (CAS: 29611-03-8) produced by liver S-9 increased approximately twofold in rats between 12 and 26 months of age. The cytochrome P450 content and the NADPH cytochrome c reductase activity of liver microsomes decreased 40-45% in rats between 12 and 26 months of age. However, the activities of UDPglucuronyltransferases and most forms of glutathione S-transferase did not change significantly with increasing age in liver microsomes and cytosol, respectively.

Aflatoxin B1↗
PubMed1987

Inhibition of aflatoxin B1 mutagenesis in Salmonella typhimurium and DNA damage in cultured rat and human tracheobronchial tissues by ellagic acid.

Ellagic acid (EA), a plant phenol found in various fruits and nuts, was examined for its ability to inhibit aflatoxin B1 (AFB1) mutagenesis in strain TA 100 of Salmonella typhimurium. In the presence of rat liver S-9 microsomal preparation, EA (1.5 microgram/plate) inhibited the number of mutations induced by AFB1 (0.5 microgram/plate) by 50%. EA at a dose of 1000 micrograms/plate inhibited the mutation frequency by greater than 90%. EA was also tested for its ability to inhibit the DNA binding and adduct formation of AFB1 in cultured explants of rat trachea and human tracheobronchus. Explants were incubated in medium containing EA at concentrations of 10, 50 and 100 microM for 16 h followed by the addition of 1 microM [3H]AFB1 and EA for 24 h. DNA was isolated by phenol extraction and hydroxylapatite chromatography. EA caused a dose-dependent inhibition in the covalent binding of AFB1 to the DNA of both the rat trachea (9-57% inhibition) and human tracheobronchus (24-79% inhibition). After acid hydrolysis of the isolated DNA, the AFB1-DNA adducts were separated by h.p.l.c. In tissues from both species, the major AFB1- DNA adducts were AFB1-N7-Gua [8,9-dihydro-8-(N7-guanyl)-9-hydroxyAFB1] and AFB1-N7-FaPyr (major) [8,9-dihydro-8- (2,6-diamino-4-oxo-3,4-dihydropyrimid-5-yl formamido)-9-hydroxyAFB1], and the formation of these adducts was reduced by 28-76% in the presence of EA. These data indicate that EA has the potential to act as a naturally occurring inhibitor of AFB1-related respiratory damage in rats and in humans.

Aflatoxin B1↗