Event: 380

Key Event Title


Activation, Pre-MIE: Metabolism of AFB1

Short name


Activation, Pre-MIE: Metabolism of AFB1

Key Event Component


Process Object Action

Key Event Overview

AOPs Including This Key Event




Level of Biological Organization


Biological Organization

Cell term


Organ term


Taxonomic Applicability


Life Stages


Sex Applicability


How This Key Event Works


The reactive exo-epoxide is formed in hepatocytes (or extra-hepatically) by metabolism of the parent AFB1 by CYP450 (Larsson et al., 1990; Larsson and Tjalve, 1993). The reactive metabolite then escapes the endoplasmic reticulum where the CYP450 is located. The reactive metabolite must evade conjugation with GSH in the cytoplasm or binding with other cytoplasmic nucleophiles. It then traverses the nuclear membrane in order to reach the cell nucleus and the nuclear DNA. Once the reactive metabolite is in the cell nucleus, it can bind with nuclear DNA to form DNA adducts.

How It Is Measured or Detected


Formation of the exo-epoxide can be produced with in vitro systems and detected using techniques for structural quantitation of AFB1 metabolites (Himmelstein et al., 2009), including liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). By using subcellular fractions (e.g., microsomes), cellular homogenates, or cells in culture, it is possible to measure formation of AFB1 exo-epoxide. Such data can also be collected from in vivo systems; samples of plasma or blood from AFB1-treated animals can be analyzed for the AFB1 exo-epoxide with similar mass spectrometric based detection systems (e.g., LC-MS/MS). Samples of blood from humans in AFB1-endemic regions have demonstrated presence of AFB1-albumin adducts, which are formed from the AFB1 exo-epoxide. AFB1-treated animals may also provide tissue samples for analysis of AFB1 exo-epoxide. Special trapping techniques may be required as the reactive AFB1 exo-epoxide metabolite has a short half-life in biological matrices.

Evidence Supporting Taxonomic Applicability


There are data across phyla demonstrating metabolic activation of AFB1 to the exo-epoxide via CYP450. This includes several mammalian species (humans, non-human primates, rats, mice) in addition to birds (turkeys) and fish (Eaton and Gallagher, 1994; IARC, 1993).



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