The Involvement of Cytochrome P4502E1 in 2‐Bromoethanol‐Induced Hepatocyte Cytotoxicity

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Abstract
The cytotoxicity of 2‐bromoethanol towards hepatocytes isolated from rats was concentration‐dependent (EC50‐100 μM, 2 hr). Bromoacetaldehyde was more toxic (EC50‐60 μM, 2 hr) and bromoacetic acid was less toxic (EC50‐150 μM, 2 hr). Glutathione (GSH) depletion occurred before cytotoxicity ensued and GSH depleted hepatocytes were more susceptible to 2‐bromoethanol. Lipid peroxidation increased steadily 1 hr after 2‐bromoethanol addition and antioxidants, iron chelators or hypoxia prevented 2‐bromoethanol induced lipid peroxidation and cell lysis. Alcohol de‐hydrogenase inhibitors, methyl pyrazole or dimethyl sulfoxide only partly prevented 2‐bromoethanol induced GSH depletion, lipid peroxidation and cytotoxicity. However, cytochrome P4502E1 (CYP2EI) inhibitors/substrates were more effective at preventing 2‐bromoethanol‐induced GSH depletion, lipid peroxidation and cytotoxicity suggesting that 2‐bromoethanol is mostly metabolically activated by CYP2E1. Also, hepatocytes isolated from CYP2E1 induced rats were more susceptible to 2‐bromoethanol and hepatocytes isolated from rats pretreated with carbon disulfide to inactivate CYP2E1 were more resistant to 2‐bromoethanol treatment. Formation of S‐(formylmethyl)glutathione during 2‐bromoethanol metabolism by microsomal mixed function oxidase in the presence of GSH was also prevented by cytochrome P4502E1 inhibitors/substrates or by Anti‐Rat CYP2E1. Furthermore, aldehyde dehydrogenase inhibitors‐cyanamide or chloral hydrate increased 2‐bromoethanol dependent hepatocyte susceptibility. This suggests that 2‐bromoethanol is preferably metabolised by CYP2E1 dependent monoxygenase to form 2‐bromoacetaldehyde which causes cell lysis as a result of GSH depletion and lipid peroxidation.