Aflatoxin activation

Foods high ia sucrose, proteia, or starch (qv) tend to biad water less firmly and must be dried to a low moisture content to obtain microbial StabiHty. For example, grain and wheat flour can support mold growth at moisture contents above 15% (wet basis) and thus are stored at moisture contents below 14%. Stored grains and oil seeds must be kept at a water activity below 0.65 because certain molds can release aflatoxias as they grow. Aflatoxins are potent carciaogens (see Food toxicants, naturally occurring). 

Internal acetals are found in several biological active natural products such as di-hydroclerodin [209] and aflatoxins as 6/2-70 [210]. An efficient formation of this functionality was described by Eilbracht and coworkers [211], using a hydroformylation of an enediol as 6/2-71 to give the tetrahydrofurobenzofurans 6/2-72 (Scheme 6/2.15). 

It is of interest to compare the shapes and sizes of various molecules with appreciable carcinogenic activity. For example, aflatoxin B] (VI), found in moldy peanuts and grain, is one of the most powerful carcinogens known. Its crystal structure was determined by van Soest and Peerdeman (46-48). 

The mode of action of this carcinogen is believed to involve epoxidation of a double bond (49), as indicated in Figure 3 in this Figure the similarities of the shapes, and particularly of the sites of activation of aflatoxin, BP and DMBA are demonstrated. Aflatoxin has functional groups at each end of the molecule, unlike an activated PAH which has functional groups only at one end of the molecule. 

Figure 3. (a) Similarities in the shapes of BP, DMBA, a base pair of guanine and cytosine, and the steroid, estradiol. In (b) the shapes of BD and DMBA (filled bonds) are compared with that of aflatoxin B] (open bonds) and the sites of activation of each to an epoxide is indicated by the arrows. 

Induced mutagenesis in Escherichia coli is an active process involving proteins with DNA replication, repair, and recombination functions. The available evidence suggests that mutations are generated at sites where DNA has been damaged and that they arise via an error-prone repair activity. In an attempt to understand what specific contributions to mutagenesis are made by DNA lesions, we have studied the mutational specificity of some carcinogens, such as benzo[a]pyrene and aflatoxin, whose chemical reactions with DNA are... 

CYP1A2. CYP1A2 has been implicated in the activation of procarcinogenic species such as aflatoxin Bl, 2-acetylaminofluorene, and other arylamines. It tends to favor aromatic substrates, both heterocyclic aromatic substrates like caffeine and aromatic substrates like phenacetin (10). In the case of caffeine, 1A2 is the major isoform catalyzing the... 

The potent carcinogen aflatoxin B1 is activated by generation of an epoxide on a dihydrofuran moiety [43]. The potent MBIs contained in grapefruit juice and in the herbal medication St J ohn s Wort are furanocoumarin compounds [44—46]. A similar moiety is also incorporated in the HIV protease inhibitor L-754,394, a potent CYP3A4 MBI [47]. 

Stott, W.T. and Sinnhuber, R.O. Trout hepatic enzyme activation of aflatoxin-B] in a mutagen assay system and inhibitory effects of PCBs. Bull. Environ. Contam. Toxicol. (1978) 19, 35. 

Aflatoxin Bi (AFB) is a mold metabolite which has been observed to be acutely toxic and carcinogenic to a wide variety of animals (5,6) and has been implicated in human primary hepatic carcinoma (7, 8). Diets deficient in protein have been reported to increase the susceptibility of mammals to acute AFB toxicity and the induction of cancer (2, 9, 10, 11, 12, 13). Increased dietary proteins have increased the carcinogenic activity of AFB fed to rats (1 4) and trout (15.). Supportive of this latter finding has been the reported direct relationship between dietary protein content and AFB-DNA adduct formation in vivo in rats (16, 17). 

Table III. Effect Dietary Casein Levels on the in vitro Activities of Trout Hepatic Cytochrome c Reductase, Aldrin Epoxidase, and the Conversion of Aflatoxin B- to Aflatoxicol3...

Soil populations and aflatoxin contamination are influenced by weather patterns, with hot dry soils favoring the Aspergillus section Flavi. In terms of geographic location, A. flavus incidence is correlated with high minimum temperatures and inversely correlated to latitude. For example, corn ears that develop at temperatures of 28 to 32°C are far more likely to be contaminated by aflatoxin than ears grown later in the season at lower temperatures. However, late planting is not economically feasible due to lower crop yields. Besides hot dry weather, the level of insect and rodent activity in an area may also substantially favor colonization and aflatoxin production. Plant fertility, density, and disease also play roles in the level of aflatoxin contamination. 

Contamination of crops and products with ochratoxin A and related metabolites is not as directly associated with a particular fungus as is the case with the aflatoxins. Ochratoxin A is also likely to occur with other mycotoxins, such as citrinin and penicillic acid or patulin. In addition, it is not certain whether ochratoxin A contamination is only a storage problem or perhaps a dual field and storage problem. In cases such as coffee crops, the use of insecticides might help to control insect activity and consequently fungal infection. Coffee-berry borers are a major insect pest which can act as vectors to carry fungal spores, resulting in crop infection and ochratoxin accumulation. 

Denissenko, M.F. et al., Quantitation and mapping of aflatoxin DNA damage in genomic DNA using aflatoxin Bi-8,9-epoxide and microsomal activation systems, Mutat. Res., 425, 205, 1999. 

Riley, J. et al., In vitro activation of the human Harvey-ras proto-oncogene by aflatoxin Bi, Carcinogenesis, 18, 905, 1997. 

Antihepatotoxic activity. A mixture of the methanol-insoluble fraction of the dried resin, fresh garlic, curcumin, ellagic acid, butylated hydroxytoluene, and butylated hydroxyanisole, administered by gastric intubation to ducklings at a dose of 10 mg/ani-mal, was active vs aflatoxin Bl-induced hepatotoxicity " . ... 

Antimutagenic activity. Water extract of the dried gum, on agar plate at a concentration of 2 mg/plate, was inactive on SalmO nella typhimurium TAIOO vs aflatoxin Bl-induced mutagenesis and a concentration of 10 mg/plate, was inactive on SalmO nella typhimurium TA98 " . Asafoetida, on agar plate at a dose of 0.5 (Xg/plate was active on Salmonella typhimurium TA98 and... 

TAIOO vs aflatoxin Bl-induced mutagenesis " . Asafoetida, on agar plate, was active on Salmonella typhimurium TAIOO and TA1535 microsomal activation-depen-dent mutagenicity of 2-acetamidofluo-rene """. 

Garg, D. K., A. C. Banerjea, and J. Verma. The role of intestinal Clostridia and the effect of asafetida (Hing) and alcohol in flatulence. Indian J Microbiol 1980 20(3) 194-197. Bordia, A., and S. K. Arora. The effect of essential oil (active principle) of asafetida on alimentary lipemia. Indian J Med Res 1975 63(5) 707-711. Soni, K. B., M. Lahiri, P. Chakcradeo, S. V. Bhide, and R. Kuttan. Protective effect of food additives on aflatoxin-induced mutagenicity and hepatocar-cinogenicity. Chem Lett 1997 115(2) 129-133. 

---