The involvement of cytochrome P4502E1 in 2-bromoethanol-induced hepatocyte cytotoxicity.

Abstract

The cytotoxicity of 2-bromoethanol towards hepatocytes isolated from rats was concentration-dependent (EC(50)100 mu M, 2 hr). Bromoacetaldehyde was more toxic (EC(50)60 mu M, 2 hr) and bromoacetic acid was less toxic (EC(50)150 mu M, 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 dehydrogenase inhibitors, methyl pyrazole or dimethyl sulfoxide only partly prevented 2-bromoethanol induced GSH depletion, lipid peroxidation and cytotoxicity. However, cytochrome P4502E1 (CYP2E1) 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.

• Authors: S Khan, C Sood, P J O'Brien
• Journal: Pharmacology & toxicology (Pharmacol Toxicol) Vol. 78 Issue 4 Pg. 241-8 (Apr 1996) ISSN: 0901-9928 [Print] Denmark
• PMID: 8861782 (Publication Type: Journal Article)

Chemical References

• Antioxidants
• Iron Chelating Agents
• Propanols
• Ethanol
• allyl alcohol
• 1-Propanol
• Cytochrome P-450 CYP2E1
• Glutathione
• ethylene bromohydrin

Topics

• 1-Propanol (toxicity)
• Animals
• Antioxidants (pharmacology)
• Biotransformation (drug effects)
• Cell Membrane (drug effects, enzymology)
• Cell Survival (drug effects)
• Chemical and Drug Induced Liver Injury (enzymology, metabolism)
• Cytochrome P-450 CYP2E1 (metabolism)
• Ethanol (analogs & derivatives, toxicity)
• Glutathione (metabolism)
• Iron Chelating Agents (pharmacology)
• Lipid Peroxidation (drug effects)
• Liver (drug effects, metabolism)
• Male
• Mass Spectrometry
• Oxidation-Reduction
• Propanols
• Rats
• Rats, Sprague-Dawley