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PubMed1990

Stable expression of human cytochrome P450IA2 cDNA in a human lymphoblastoid cell line: role of the enzyme in the metabolic activation of aflatoxin B1.

A human lymphoblastoid cell line stably expressing a human cytochrome P450IA2 cDNA was developed. This recombinant cell line displayed P450IA2 protein and estradiol 2-hydroxylase activity, neither of which was detected in the parental cell line. The recombinant cell line was also approximately 1000-fold more sensitive to the cytotoxicity and mutagenicity of the carcinogenic mycotoxin aflatoxin B1 than was the parent cell line. The increase in mutagenicity was supported by a corresponding increase in the level of aflatoxin B1 binding to DNA in cells expressing P450IA2 relative to control cells.

Aflatoxin B1↗
PubMed1975

Characterization of monosomes produced by aflatoxin B1.

A single injection of 1.5 mg aflatoxin B1 per kg body weight produced approx. 70% disaggregation of rat liver polysomes into monosomes within 18 h. Isolated monosomes dissociated into 40 S subunits during centrifugation in linear sucrose gradients containing 0.3 M KCI. The 4 S to 5 S molar RNA ratio of the monosomes was calculated to be 0.6, indicating 0.6 tRNA and/or aminoacyl tRNA molecule per ribosome; no peptidyl tRNA was present. These results suggest that a single injection of affatoxin B1 produces monosomes which resemble runoff ribosomes.

Aflatoxins↗
PubMed2005

Taxonomic comparison of three different groups of aflatoxin producers and a new efficient producer of aflatoxin B1, sterigmatocystin and 3-O-methylsterigmatocystin, Aspergillus rambellii sp. nov.

Accumulation of the carcinogenic mycotoxin aflatoxin B, has been reported from members of three different groups of Aspergilli (4) Aspergillus flavus, A. flavus var. parvisclerotigenus, A. parasiticus, A. toxicarius, A. nomius, A. pseudotamarii, A. zhaoqingensis, A. bombycis and from the ascomycete genus Petromyces (Aspergillus section Flavi), (2) Emericella astellata and E. venezuelensis from the ascomycete genus Emericella (Aspergillus section Nidulantes) and (3) Aspergillus ochraceoroseus from a new section proposed here: Aspergillus section Ochraceorosei. We here describe a new species, A. rambellii referable to Ochraceorosei, that accumulates very large amounts of sterigmatocystin, 3-O-methylsterigmatocystin and aflatoxin B1, but not any of the other known extrolites produced by members of Aspergillus section Flavi or Nidulantes. G type aflatoxins were only found in some of the species in Aspergillus section Flavi, while the B type aflatoxins are common in all three groups. Based on the cladistic analysis of nucleotide sequences of ITS1 and 2 and 5.8S, it appears that type G aflatoxin producers are paraphyletic and that section Ochraceorosei is a sister group to the sections Flavi, Circumdati and Cervini, with Emericella species being an outgroup to these sister groups. All aflatoxin producing members of section Flavi produce kojic acid and most species, except A. bombycis and A. pseudotamarii, produce aspergillic acid. Species in Flavi, that produce B type aflatoxins, but not G type aflatoxins, often produced cyclopiazonic acid. No strain was found which produce both G type aflatoxins and cyclopiazonic acid. It was confirmed that some strains of A. flavus var. columnaris produce aflatoxin B2, but this extrolite was not detected in the ex type strain of that variety. A. flavus var. parvisclerotigenus is raised to species level based on the specific combination of small sclerotia, profile of extrolites and rDNA sequence differences. A. zhaoqingensis is regarded as a synonym of A. nomius, while A. toxicarius resembles A. parasiticus but differs with at least three base pair differences. At least 10 Aspergillus species can be recognized which are able to biosynthesize aflatoxins, and they are placed in three very different clades.

Aflatoxin B1↗
PubMed1996

Action of curcumin on the cytochrome P450-system catalyzing the activation of aflatoxin B1.

Curcumin, in a dose-dependent manner, inhibited the formation of covalent adduct between aflatoxin B1 and DNA, as catalyzed by microsomes or a reconstituted microsomal monooxygenase system. Its effect on the cytochrome P450-system was investigated in the latter system. The inhibition (50%) of aflatoxin B1-DNA adduct formation by curcumin in this system could be reversed by increasing the amount of cytochrome P450 but not by that of NADPH-cytochrome P450 reductase. Curcumin inhibited the reductase activity when measured by the reduction of cytochrome C but not when measured by the reduction of dichlorophenolindophenol, an artificial electron acceptor. These results, as well as the reversal of curcumin-induced inhibition of P450 reductase activity by higher amounts of cytochrome C, indicated a strong affinity of curcumin towards cytochromes. This was further substantiated from the observation that curcumin-pretreated cytochrome P450 had reduced ability to catalyze aflatoxin B1-DNA adduct formation in the reconstituted system. Curcumin, thus, may inhibit chemical carcinogenesis by modulating cytochrome P450 function.

Aflatoxin B1↗
PubMed1980

Inhibition of microsome-mediated binding of aflatoxin B1 to DNA by glutathione S-transferase.

Hamster liver microsome-mediated [14C]aflatoxin B1 binding to DNA is inhibited by 105,000 X g liver supernatant fraction. Absolute requirement of glutathione for the inhibitory activity of the dialyzed supernatant and irreversible loss of the inhibitory activity by the heat-treated supernatant indicate involvement of glutathione S-transferase. Concomitant with inhibition of aflatoxin B1-DNA binding, the formation of an aflatoxin B1-glutathione conjugate is indicated.

Aflatoxins↗
PubMed1984

Effect of butylated hydroxytoluene on the disposition of [14C]aflatoxin B1 in the lactating rat.

The distribution and metabolism of an ip dose of [14C]aflatoxin B1 (AFB1) were studied in lactating Sprague-Dawley rats fed for the previous 13 days on a diet containing 0.5% butylated hydroxytoluene (BHT). Compared with ingestion of a BHT-free diet, treatment with BHT increased the biotransmission of AFB1 metabolites, predominantly aflatoxin M1 (AFM1), into the mammary gland and its content of milk, decreased AFB1 binding to liver nuclear DNA and enhanced the excretion of water-soluble metabolites of AFB1, all measured 6 hr after an oral dose of [14C]AFB1. These changes are related to the induction by BHT of hepatic enzymes involved in the transformation and detoxification of AFB1. The results suggest that exposure to BHT may protect the lactating animal from the carcinogenic effect of AFB1 but may increase the risk of exposure of the newborn infant to the carcinogenic metabolite AFM1.

Aflatoxin B1↗
PubMed1986

Aflatoxin B1 binding to plasma albumin and liver DNA upon chronic administration to rats.

The hepatocarcinogen aflatoxin B1 (AFB1) was administered to male Wistar rats by oral intubation in either single or repeated doses and the binding to plasma protein and liver DNA determined. Twenty-four hours after a single dose (3.5-200 micrograms/kg AFB1) a constant ratio was found between levels of aflatoxin bound to plasma protein and that bound to liver DNA. In total 0.98-2.15% of the administered dose was bound to the plasma protein at this time point. In the chronic study rats received two doses of 0.5 microgram AFB1/day and groups of animals were killed on days 2, 3, 7, 14, 21 and 24. Binding of aflatoxin to plasma protein accumulated to a level 3-fold higher than that seen after a single dose. Levels of binding reached a plateau between days 7 and 14 of treatment and then remained stable until the end of the experiment. Binding to DNA also accumulated, 2.5-fold and in parallel to plasma protein, binding reached a plateau between days 7 and 14 of treatment. In both the chronic and acute studies fractionation of the plasma proteins by Sephadex G-200 chromatography showed that all detectable bound aflatoxin was associated with a single peak corresponding to albumin. Thus, a constant ratio was observed, after chronic or single exposure, between the concentration of plasma albumin-bound aflatoxin and that bound to DNA of the liver, the target organ for carcinogenesis by AFB1. In order to investigate the proposed role of AFB1 in the aetiology of primary hepatocellular carcinoma in man it would be of great value to have a method for assessing long-term human exposure at an individual level. The relevance of the observations presented in this paper are discussed in the light of such a requirement.

Aflatoxin B1↗
PubMed1977

Thin layer chromatographic determination of aflatoxin B1 in eggs.

A method for determining aflatoxin in dairy products was modified for eggs, initially by additional cleanup steps. The modified method proved practical for use in survey analyses and was sufficiently sensitive to detect aflatoxin B1 at levels less than 1 ng/g in eggs from hens on experimentally contaminated feed and in spiked eggs; interfering compounds in eggs received from many different producing areas were eliminated. Although recovery was greater than 75% when the aflatoxin was extracted immediately after spiking, recovery was usually less than 30% when the aflatoxin was extracted after more than 24 hr. Adding sodium chloride, sodium sulfate, or urea to the extracting solvent remedied this defect, which is thought to be related to the binding of aflatoxin to egg protein.

Aflatoxins↗
PubMed1995

Effects of natural polyphenols on aflatoxin B1 activation in a reconstituted microsomal monooxygenase system.

Covalent adduct formation between aflatoxin B1 and DNA, as catalyzed by a reconstituted microsomal monooxygenase system containing purified cytochrome P450 and NADPH-cytochrome P450 reductase, was observed to be inhibited by certain polyphenolic compounds of natural origin. Polyhydroxylated flavonoids were found to be more effective than phenolic acids and displayed dose-dependent inhibition. The inhibition (50%) could be reversed by increasing the amount of cytochrome P450 but not by increasing the amount of reductase. Each polyphenol inhibited NADPH-cytochrome P450 reductase activity as measured by reduction of cytochrome C. This inhibition could be reversed with higher amounts of cytochrome C. This inhibition, however, could not be reversed if an artificial electron acceptor, dichlorophenolindophenol, was used in place of cytochrome C. These results suggest a strong affinity of polyphenols toward cytochromes. This conclusion was further supported from the observation that pretreatment of cytochrome P450 with each polyphenol reduced its ability to catalyze aflatoxin B1-DNA adduct formation in the reconstituted system. Natural polyphenols, thus, may have the ability to modulate chemical carcinogenesis by modulating cytochrome P450 function.

2,6-Dichloroindophenol↗
PubMed1998

Identification of amino acid residues essential for high aflatoxin B1-8,9-epoxide conjugation activity in alpha class glutathione S-transferases through site-directed mutagenesis.

Mice constitutively express glutathione S-transferase mGSTA3-3 in liver. This isoform possesses uniquely high conjugating activity toward aflatoxin B1-8,9-epoxide (AFBO), thereby protecting mice from aflatoxin B1-induced hepatocarcinogenicity. In contrast, rats constitutively express a closely related GST isoenzyme, rGSTA3-3, with low AFBO activity and, therefore, are sensitive to aflatoxin B1 exposure. Although the two GSTs share 86% sequence identity and have similar catalytic activities toward 1-chloro-2,4-dinitrobenzene (CDNB), they have an approximately 1000-fold difference in catalytic activity toward AFBO. To identify amino acids that confer high activity toward AFBO, non-conserved rGSTA3-3 residues were replaced with mGSTA3-3 residues in two regions believed to form the substrate binding site. Twenty-one mutant rGSTA3-3 enzymes were generated by site-directed mutagenesis using combinations of nine different residues. Except for the E208D mutant, single mutations of rGSTA3-3 produced enzymes with no detectable AFBO activity. Generally, AFBO conjugation activity increased in additive fashion as mGSTA3-3 residues were introduced into the rGSTA3-3 enzyme with the six site mutant E104I/H108Y/Y111H/L207F/E208D/V217K displaying the highest AFBO activity (40 nmol/mg/min) of all the mutant enzymes. When this mutant enzyme was further modified by three additional substitutions (D103E/I105M/V106I) AFBO conjugation activity decreased 14-fold to 2. 8 nmol/mg/min. Although wild-type mGSTA3-3 AFBO conjugation activity (265 nmol/mg/min) could not be obtained by our rGSTA3-3 mutants, we were able to identify six mGSTA3-3 residues; Ile104, Tyr108, His111, Phe207, Asp208, and Lys217 that, when collectively substituted into rGSTA3-3, substantially increased (>200-fold) glutathione conjugation activity toward AFBO.

Aflatoxin B1↗
PubMed1995

Determination of aflatoxins in groundnut meal by high-performance liquid chromatography: a comparison of two methods of derivatisation of aflatoxin B1.

A comparison has been made between pre-column and post-column derivatisation of aflatoxin B1 (AFB1) during estimation by high-performance liquid chromatography of this toxin in groundnut meal. The effect of the use of different derivatisation reagents on the quantification of aflatoxin B2 (AFB2) has also been evaluated. Both AFB1 and AFB2 were analysed at eight levels of artificial contamination. Five replicate analyses were carried out at each level on both groundnut meal extract (acetone-water, 85:15, v/v) and extraction solvent alone. A statistical evaluation of the results gave limits of detection of 1.1 and 0.3 micrograms/kg for AFB1 and AFB2 respectively, using pre-column derivatisation compared with 1.5 and 0.8 micrograms/kg for the post-column method. Recoveries of over 90% from the spiked groundnut meal extracts were achieved for both derivatisation methods.

Aflatoxin B1↗
PubMed1991

Mouse strain differences in glutathione S-transferase activity and aflatoxin B1 biotransformation.

Previous studies have suggested that mice are resistant to the carcinogenic effects of aflatoxin B1 (AFB1) and that this resistance is largely the result of expression of an isoenzyme of glutathione S-transferase (GST) with high activity toward AFB1-8,9-epoxide. Significant interstrain differences in cytosolic GST activities toward a variety of substrates have been reported in mice. If such differences exist for the conjugation of AFB1-8,9-epoxide, then there may be significant mouse strain differences in susceptibility to AFB1-induced hepatocarcinogenicity. The hepatic microsomal and cytosolic biotransformation of AFB1 was studied in 8 different strains of mice fed a purified diet. GST-mediated conjugation of AFB1-8,9-epoxide with glutathione and GST activity toward 1-chloro-2,4-dinitrobenzene (CDNB), 1,2-dichloro-4-nitrobenzene (DCNB), ethacrynic acid (ECA) and cumene hydroperoxide (CHP) were determined with cytosolic fractions from 8-10 pooled livers. Specific activities of cytochrome-P-450-mediated oxidation of AFB1 to aflatoxin Q1 (AFQ1), aflatoxin M1 (AFM1), and aflatoxin P1 (AFP1), as well as the reactive intermediate AFB1-8,9-epoxide, were determined with hepatic microsomal fractions from each mouse strain. No striking differences in specific activity between mouse strains were observed for any of the P-450- or GST-mediated enzymatic pathways measured, although some statistically significant differences were found. GST specific activities toward AFB1-8,9-epoxide, CDNB, DCNB, ECA and CHP ranged from 1.5-2.1, 2,830-5,370, 81-144, 38-69 and 32-73 nmol/mg protein/min, respectively. The rate of formation of AFB1-8,9-epoxide ranged from 208 to 465 pmol/mg protein/min. The specific activities of AFQ1,AFM1, and AFP1 formation by microsomes ranged from 36-70, 161-326, and 252-426 pmol/mg protein/min, respectively. Mice fed a standard rodent chow diet showed evidence of microsomal and cytosolic enzyme induction when compared to mice fed a purified diet. The lack of substantial differences in enzyme specific activities between mouse strains suggests that interstrain variations in the hepatocarcinogenic effects of AFB1 in mice should not be large.

Aflatoxin B1↗
PubMed1989

Early influence of aflatoxin B1 on the functional state of isolated rat hepatocytes.

The early effects (60 min) of aflatoxin B1 (AFB1) on membrane permeability and carbohydrate metabolism of liver cells were studied in fresh suspensions of rat hepatocytes. Evaluation by trypan blue exclusion, enzyme leakage, glycogen synthesis or degradation, and glyconeogenesis were chosen as viability tests. The results obtained showed an increase of lactate dehydrogenase (LDH), alanine aminotransferase (GPT) and aspartate aminotransferase (GOT) released into the medium and also an increase in the number of stained cells. These changes were significant at about 18 nmol/10(6) cells of AFB1, while a remarkable effect of the toxin on glyconeogenesis and glycogen synthesis or degradation was observed at 9 nmol/10(6) cells, doses commonly used for in vitro studies.

Aflatoxin B1↗
PubMed1987

Ethoxyquin alone induces preneoplastic changes in rat kidney whilst preventing induction of such lesions in liver by aflatoxin B1.

Pretreatment of Fischer 344 rats with the antioxidant ethoxyquin (EQ), followed by administration of aflatoxin B1 (AFB1) in the continuing presence of EQ was used to examine the effect of the antioxidant on liver and kidney. EQ (0.5% in diet) completely prevented the formation of AFB1-induced preneoplastic liver lesions as judged by morphological alteration, or by markers such as gamma glutamyl transpeptidase, glutathione S-transferase P or J1, an unknown membrane-bound antigen. While protection was afforded to the liver, EQ alone caused severe damage to the kidney. Many changes were those of chronic glomerulonephrosis, such that EQ appeared to accelerate the ageing process. In addition, many hyperplastic and putative preneoplastic tubules were visible, suggesting that EQ may be exerting a carcinogenic effect in the kidney.

Aflatoxin B1↗