In an experimental model of liver cirrhosis, marked increases in ER proteasome content in rat livers were observed 5h after acute i.p. injection of the hepatotoxicant CCl 4 . To confirm the role of CYP2E1 in mediating protein misfolding/damage in the ER via its metabolism of CCl 4 , 293T cells stably transfected with human CYP2E1 were exposed to CCl 4 and cell ER fractions assessed for ubiquitination. Increases in ER ubiquitin conjugates were noted in CYP2E1/293T cells treated with CCl 4 and not in controls, suggesting these effects are CYP2E1 specific. Finally, the role of CYP2E1 in ER homeostasis was investigated by examining the unfolded protein response (UPR). When exposed to CCl 4 , CYP2E1/293T cells but not 293T or CYP1A2/293T cells showed rapid induction of the UPR-inducible ER chaperone BiP. Collectively, the data presented suggest that CYP2E1 is capable of inducing significant ER protein damage and stress via its catalytic activation of pro-oxidants.