Objective: Acrylamide (AA), a probable human carcinogen, is present in fried and baked starch-rich food. In vivo, the substance is partly biotransformed to glycidamide (GA), which may account for carcinogenic effects. Existing data suggest an important but not exclusive contribution of CYP2E1 to GA formation. The aim of this project was to derive respective enzyme kinetic parameters for CYP2E1 and to assess a possible role of other important human CYPs for this reaction in vitro.
Methods: AA (0.2-20 mM) was incubated with human liver microsomes (HLM) and human cytochrome P450 enzymes (supersomes™). GA was quantified by a specific LC-MS/MS method. Enzyme kinetic parameters were estimated assuming a single binding site. Furthermore, inhibition experiments were performed with diethyldithiocarbamate (DDC), a potent inhibitor of CYP2E1.
Results: The mean ± SD maximum formation rate (Vmax) and Michaelis-Menten constant (Km) for GA formation in HLM were 199 ± 36 pmol GA/mg protein/min and 3.3 ± 0.5 mM, respectively. In AA incubations with supersomes™, only for CYP2E1 measurable GA formation was detected in all tested AA concentrations (Vmax and Km were 5.4 nmol GA/nmol CYP2E1/min and 1.3 mM, respectively). Inhibition constant (IC50) of DDC was 3.1 ± 0.5 µM for HLM and 1.2 ± 0.2 µM for CYP2E1 supersomes™. Therefore, relevant participation of CYPs other than CYP2E1 in the metabolism of AA to GA in humans does not seem likely.
Conclusion: Our results confirm the major role of CYP2E1 in GA formation from AA, albeit with low affinity and low capacity. Further studies are needed to identify other pathways of GA formation.
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