We demonstrated before that CYP2E1 and ADH expressed in human brain endothelial cells generate ROS after EtOH exposure [12]. Here, we present evidence that primary human neurons show 3-fold induction of CYP2E1 activity after EtOH treatment, and CYP2E1 activation parallels increased ROS and NO production. These data complement the findings that ADH mRNA level was detected in human brain tissue [45]. Our results suggest that brain cells including neurons can metabolize alcohol, thereby contributing to elevated oxidative stress commonly observed in alcoholics. These findings also support the idea that EtOH metabolism results in end-organ injury. Although the tonic inhibitory current mediated by neuronal GABA-A receptor α1/δ subunit partnership is highly sensitive to low EtOH concentration [46], the molecular site of action or the binding site of the EtOH on receptor protein is unknown. It is generally accepted that direct effects of alcohol (nonmetabolized EtOH) include alteration of neuronal lipid bilayer membrane fluidity and permeability that considerably affect the ion channel conductance such as passive potassium channel [47,48]. It has been shown in neurovascular components that it is the reactive EtOH metabolites that act as the signaling molecules (second messengers) in triggering the activation of cell signaling pathways [15].
