The role of aflatoxin metabolism in its toxic lesion

Campbell, T. C.; Hayes, Jeffrey A.

doi:10.1016/0041-008x(76)90282-9

Cited by 194 publications

(45 citation statements)

References 75 publications

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“…The metabolism and the biochemical effects of AFB are well documented and reviewed (Wogan, 1968(Wogan, , 1969(Wogan, , 1973Campbell & Hayes, 1976). A major AFB-nucleic acid adduct has been identified recently in vitro and in vivo (Essigmann et al, 1977;Martin & Garner, 1977;Lin et al, 1977;Croy et al, 1978).…”

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confidence: 99%

Sequential biochemical and histological changes in rats treated with aflatoxin B1

Yin¹,

Kao²,

Lee³

1980

Br J Cancer

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Summary.-Thirteen biochemical parameters (viz. glucose, calcium, inorganic phosphorus, urea nitrogen, uric acid, cholesterol, albumin, total protein, total bilirubin, alkaline phosphatase, lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase) were determined in serum and partly in liver of rats 1-28 days after i.p. aflatoxin B1 (AFB) (3 mg/kg). Histological examinations of the liver were also made in parallel to the biochemical studies. In the serum, enzyme activities and total bilirubin level increased and peaked on the 2nd day, while other parameters showed diverse changes after AFB treatment. On the other hand, activities of aspartate aminotransferase and alanine aminotransferase in the liver significantly decreased and reached a minimum on the 2nd day after AFB administration. The depression of the liver enzyme activities persisted over 7 days. The liver protein content also reduced transiently during 1-1-5 days. However, all biochemical parameters returned to normal levels 2 weeks after treatment, and remained so throughout the rest of experimental period. Histological changes in the liver were very similar to those reported by others.

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confidence: 99%

Sequential biochemical and histological changes in rats treated with aflatoxin B1

Yin¹,

Kao²,

Lee³

1980

Br J Cancer

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“…Recent studies on the metabolism of AFB1 have resulted in the isolation and identification of numerous metabolites, all of minor structural variations but significantly different biological activity relative to the parent compound (12).…”

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Mutagenicity of aflatoxins related to their metabolism and carcinogenic potential.

Wong¹,

Hsieh²

1976

Proc. Natl. Acad. Sci. U.S.A.

221

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Aflatoxins and their animal biotransformation products were screened for carcinogenic potential using the Ames' in vitro microbial detection system for carcinogens as bacterial mutagens [B. N. Ames et aL (1973) Proc (1). The four naturally occurring AFs, aflatoxins B1 (AFB1), B2 (AFB2), G1 (AFG1), and G2 (AFG2), when administered as mixtures, were a potent class of animal hepatocarcinogens (2-6). They have been also associated with neoplastic formations in tissues and organs other than the liver (3,(6)(7)(8)(9).Tests with rats (10) and rainbow trout (11) have revealed that AFB1 is a potent hepatocarcinogen; AFG1 is also considerably carcinogenic, but AFB2 and AFG2 possess much lower activity. Recent studies on the metabolism of AFB1 have resulted in the isolation and identification of numerous metabolites, all of minor structural variations but significantly different biological activity relative to the parent compound (12).Among these metabolites, aflatoxins Q, (AFQ1), M1 (AFM1), Bk (AFBa), and P1 (AFP1), aflatoxicol (AFL), and aflatoxicol H1 (AFLH1) (Table 1) are the biotransformation products of AFB1 when the latter is incubated with liver preparations and a NADPH-generating system (13-17). Since evidence has indicated that AFB1 requires metabolic activation for its toxic, mutagenic, and/or carcinogenic activity (18)(19)(20)(21)(22), the toxicity of each metabolite has been of great interest in the search for the active molecular species. Attempts have been made to correlate the relative activity of the different metabolic pathways and the variations in the species susceptibility to aflatoxicosis (16,23 (24,25). The analysis of the known major AF metabolites in our study permits an observation of the structureactivity relationships as related to the carcinogenic potential of the AFs. MATERIALS AND METHODSChemicals are obtained as follows: AFBI, AFG1, AFB2, and AFG2 were purchased from Makor Chemicals, Ltd., Jerusalem, Israel. AFM1, AFQ1, and AFH1 were prepared by biotransformation of AFB1 using monkey liver homogenates (14, 17). AFL was prepared by a similar biotransformation method to be published elsewhere. AFB2k and AFGk were chemically synthesized from AFB1 with dilute acid (27). AFP1 was a chemically synthesized product kindly provided by G. N. Wogan, Massachusetts Institute of Technology, Cambridge, Mass. The purity and identity of all AFs was checked by fluorodensitometric analysis of thin-layer chromatography plates and mass spectrometry. In addition, AFQ1, AFM1, AFH1, and AFB2k were checked by high-pressure liquid chromatography (28). All biochemicals, NADP+, glucose 6-phosphate, histidine, and biotin, were purchased from Sigma Chemicals, St. Louis, Mo.The bacterial tester strain, Salmonella typhimurium strain TA 98 (21), was the generous gift of B. N. Ames, University of California, Berkeley. The bacteria were stored and grown as outlined by McCann et al. (21). The hepatic S-9 enzyme preparation was prepared from Charles River male white rats (200-250 g) and utilized according to procedur...

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“…This double bond makes all the difference, as it allows detoxifying systems (cytochrome P 450 ) in the body to convert it to an epoxide by cytochrome P 450 s, specifically CYP3A4, CYP3A5, and/or CYP1A2 (Gallagher et al, 1994; to the exo-8, 9-epoxide, which ironically is the "activated" form of the molecule that can form adducts with deoxyribonucleic acid (DNA) leading to guanine nucleotide substitutions (Lilleberg et al, 1992). In passing it is also important to note that cytochrome P450 types also convert AFB 1 to other derivatives e.g., AFM 1 , AFP 1 and Q 1 (Campbell and Hayes 1976). The epoxide is a good alkylating agent and can react with bases such as those in DNA and RNA to form the AF-alkylated form.…”

Section: Toxicology Of Afbmentioning

confidence: 99%