Aflatoxin B1

DESCRIBE THE MECHANISM OF ACTION OF AFLATOXIN B1 INDUCTION OF CARCINOGENESIS

The earliest symptoms of the disease are lethargy and muscular weakness followed by death. The term aflatoxin now refers to group of bisfuranocoumarin metabolites isolated from strains of A. flavus group of fungi. The toxic material derived from the fungus A. flavus was given the name "aflatoxin" in 1962. Aflatoxins fluoresce strongly in ultra violet light. The major members are designated as B1, B2, G1 and G2. B1 and B2 fluoresces blue, while Gl and G2 fluoresces green.

At least 14 mycotoxins are known in the laboratory to be carcinogens, including several aflatoxins, sterigmatocystin, cyclochlorotine, griseofulvin, and patulin. With the exception of cyclochlorotine they are all active on the DNA level. Two types of interaction have been shown to occur between aflatoxins and nucleic acids. One is a non—covalent, weak and reversal binding, the other is an irreversible covalent binding requiring mammalian metabolizing systems. Most of the carcinogenic and genetic activities of aflatoxins and related compounds such as sterigmatocystin have been observed with metabolically activated mycotoxins. Crucial for the covalent binding is the C —C unsaturated bond, which means that aflatoxins B1 and C1 are more active than B2 and C2. A strong correlation can be found between carcinogenicity, mutagenicity and the extent of covalent DNA binding among aflatoxins and their metabolites and precursors. Guanine in the DNA is the principal target for the attack of activated aflatoxins. The formation of mutations is made possible by the covalent binding to DNA which may lead to cancer. A direct interaction between aflatoxin and nuclear DNA as a primary mechanism of action has been questioned. It has been demonstrated that the aflatoxin B1 induced inhibition of DNA synthesis was due primarily to reduction of thymidine transport into the cell and not of decreased DNA template activity. However, as normal cells do not need external thymidine; they synthesize their own thymidine from uridine,  the significance of this transport for the mechanism by which aflatoxins inhibit nucleic acids in normal cells may be questioned.

Recent work by Niranjan et al. showed that aflatoxin B1 administered to experimental animals is covalently linked to liver mitochondria more efficiently than to nuclear DNA. The concentration of carcinogenic adducts in mitochondrial DNA remains unchanged even after 24 hours, possibly because of lack of excision repair. In consequence, mitochondrial transcription and translation remain inhibited for up to 24 hours. The authors suggest that this long term inhibition of mitochondrial biosynthetic processes and possible mitochondrial mutational events may contribute to the carcinogenic process. In view of the large number of mitochondria per cell, this hypothesis is obviously open to certain objections.