Reactome | Aflatoxin activation and detoxification

Aflatoxin activation and detoxification

Stable Identifier

R-HSA-5423646

Type

Pathway

Species

Homo sapiens

ReviewStatus

5/5

Locations in the PathwayBrowser

Expand all

General

SBML | | PDF

SVG | | PPTX | SBGN

Click the image above or here to open this pathway in the Pathway Browser

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.

Literature References

PubMed ID	Title	Journal	Year
19514968	Biological degradation of aflatoxins Wu, Q, Jezkova, A, Dohnal, V, Kuca, K, Pavlikova, L, Yuan, Z	Drug Metab. Rev.	2009
9675258	Activation and detoxication of aflatoxin B1 Johnson, WW, Guengerich, FP, Yamazaki, H, Ueng, YF, Langouët, S, Shimada, T	Mutat. Res.	1998
12435844	The toxicology of aflatoxins as a basis for public health decisions Turner, PC, Wild, CP	Mutagenesis	2002
	Aflatoxins - Biochemistry and Molecular Biology Guevara-Gonzalez, G		2011
23599745	Aflatoxin B1-induced hepatocellular carcinoma in developing countries: Geographical distribution, mechanism of action and prevention Zhang, ZG, Hamid, AS, Tesfamariam, IG, Zhang, Y	Oncol Lett	2013