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Aflatoxin activation and detoxification

Summary

Organism

Homo sapiens (human)

Reactome

R-HSA-5423646

PubChem

R-HSA-5423646

Description

Aflatoxins are among the principal mycotoxins produced as secondary metabolites by the molds Aspergillus flavus and Aspergillus parasiticus that contaminate economically important food and feed crops (Wild & Turner 2002). Aflatoxin B1 (AFB1) is the most potent naturally occurring carcinogen known and is also an immunosuppressant. It is a potent hepatocarcinogenic agent in many species, and has been implicated in the etiology of human hepatocellular carcinoma. Poultry, especially turkeys, are extremely sensitive to the toxic and carcinogenic action of AFB1 present in animal feed, resulting in multi-million dollar losses to the industry. Discerning the biochemical and molecular mechanisms of this extreme sensitivity of poultry to AFB1 will help with the development of new strategies to increase aflatoxin resistance (Rawal et al. 2010, Diaz & Murcia 2011).

AFB1 has one major genotoxic metabolic fate, conversion to AFXBO, and several others that are less mutagenic but that can still be quite toxic. AFB1 can be oxidised to the toxic AFB1 exo 8,9 epoxide (AFXBO) product by several cytochrome P450 enzymes, especially P450 3A4 in the liver. This 8,9 epoxide can react with the N7 atom of a guanyl base of DNA to produce adducts by intercalating between DNA base pairs. The exo epoxide is unstable in solution, however, and can react spontaneously to form a diol that is no longer reactive with DNA. The diol product in turn undergoes base-catalysed rearrangement to a dialdehyde that can react with protein lysine residues. AFB1 can also be metabolised to products (AFQ1, AFM1, AFM1E) which have far less genotoxic consequences than AFB1. The main route of detoxification of AFB1 is conjugation of its reactive 8,9-epoxide form with glutathione (GSH). This reaction is carried out by trimeric glutathione transferases (GSTs), providing a chemoprotective mechanism against toxicity. Glutathione conjugates are usually excreted as mercapturic acids in urine (Guengerich et al. 1998, Hamid et al. 2013). The main metabolic routes of aflatoxin in humans are described here.

Click on a node on the pathway to see its details. Glycoproteins are marked with a glycoprotein icon in their name.

SPV: a JavaScript Signaling Pathway Visualizer, Bioinformatics, 2018

Displaying **all 10** entries
UniProt ID	Protein Name	Gene Symbol	Pathway Viewer
A6NGU5	Putative glutathione hydrolase 3 proenzyme	GGT3 GGT3P	view
P05177	Cytochrome P450 1A2	CYP1A2	view
P16444	Dipeptidase 1	DPEP1 MDP RDP	view
P19440	Glutathione hydrolase 1 proenzyme	GGT GGT1	view
P20815	Cytochrome P450 3A5	CYP3A5	view
P36269	Glutathione hydrolase 5 proenzyme	GGT5 GGTLA1	view
Q6P531	Glutathione hydrolase 6	GGT6	view
Q8NHP1	Aflatoxin B1 aldehyde reductase member 4	AFAR3 AKR7A4 AKR7L	view
Q9H4A9	Dipeptidase 2	DPEP2 UNQ284/PRO323	view
Q9UJ14	Glutathione hydrolase 7	GGT7 GGTL3 GGTL5	view

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