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Metabolism of AFB1, Production of Reactive Electrophiles leads to Formation, Pro-mutagenic DNA Adducts
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|AFB1: Mutagenic Mode-of-Action leading to Hepatocellular Carcinoma (HCC)||adjacent||High||Ted Simon (send email)||Open for citation & comment||EAGMST Under Review|
Life Stage Applicability
Key Event Relationship Description
AFB1 must be metabolized via Cytochromes P450 to a specific highly reactive form of AFB1, the exo-epoxide AFB1-8,9-epoxide, in order for DNA binding and formation of a pro-mutagenic DNA adduct to occur. CYP3A4 forms only the exo-form of this reactive epoxide. CYP1A2, inducible in liver, forms both the exo- and the endo-epoxides apparently with a lower Vmax and higher Km than CYP3A4 in human liver (Degen and Neumann,1981; Groopman and Kensler, 2005; Guengerich et al., 1996; Ueng et al., 1995).). Figure X, taken from Pottenger et al., 2014, depicts the metabolism of AFB1. The activated metabolite, exo-epoxide, must then travel from the endoplasmic reticulum, (site of CYP450 enzyme and exo-epoxide of formation) to the nucleus, in order to bind to DNA to form the pro-mutagenic N7-AFB1-G adduct. This can further react to form the AFB1 FAPy adduct.
Evidence Supporting this KER
The biological plausibility of the KER pre-MIE to MIE is strong; without the specific, CYP-450-mediated metabolic activation of AFB1 to the exo-epoxide, the necessary pro-mutagenic N7-AFB1-G adduct will not form, and the sequence of key events will not continue further.
Uncertainties and Inconsistencies
The available data do not include dose-response data for activation of AFB1 to the key metabolite, exo-8,9-epoxide, which precludes presenting a quantitatively defined relationship between activation and formation of the pro-mutagenic N7-AFB1-G adducts. However, this does not diminish the certainty in the essentiality of this KER.
There are some data to inform the persistence of N7-AFB1-G and its transformation to AFB1-FAPy (Brown et al., 2006; Croy and Wogan, 1991a), but more detailed data, including dose-response data, would be useful.
No inconsistencies were identified vis-à-vis this KER; the conundrum of the high AFB1 metabolic capacity of the mouse and its resistance to the adverse outcome has been investigated and demonstrated to be due to the high rate of detoxication of the exo-epoxide by mouse GSTs (Degen and Neumann, 1981; Monroe and Eaton, 1987, 1988).
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
The requirement for metabolism of AFB1 to a specific reactive form is applicable to all mammalian systems evaluated; it is also applicable to certain birds (turkeys, etc.) (Gregory et al., 1983; IARC, 1993). Humans, non-human primates, rats, mice, poultry, and fish have all demonstrated susceptibility to AFB1-induced liver tumors (Asplin and Canaghan, 1961; Eaton and Gallagher, 1994; Guengerich et al., 1996). Species that preferentially metabolize AFB1 to the exo-8,9-epoxide are more susceptible to AFB1 carcinogenicity.
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