INDUCTION MECHANISMS OF CYTOCHROME-P450 2E1 IN LIVER - INTERPLAY BETWEEN ETHANOL TREATMENT AND STARVATION

Chronic ethanol exposure causes marked induction of the ethanol-induci ble cytochrome P450 (CYP) 2E1 isozyme in the centrilobular liver regio n, where alcoholic damage commonly is initiated. In contrast to most o ther CYP forms, which are ligand-activated at the transcriptional leve l, ethanol induction of CYP2E1 has been found to be post-translational . However, transcriptional activation of the CYP2E1 gene was recently described in fed animals maintained at very high ethanol levels. To fu rther evaluate mechanisms of ethanol-mediated CYP2E1 induction we comp ared the effect of short-term heavy-ethanol treatment and fasting on C YP2E1 mRNA, protein and catalytic activity. High blood-ethanol levels (20-70 mM) were maintained for 3 days by regular alcohol intubations t o fed or fasted rats. During this period, the amount of liver CYP2E1 a poprotein increased a maximum of 20-fold and catalytic activity 16-fol d, both in fed and fasted animals, whereas starvation alone caused onl y a 4- to 5-fold increase. By comparison, the amount of CYP2E1 mRNA, a s assayed both by Northern blot and slot blot, was significantly incre ased (5- to 6-fold) by ethanol only in fasted rats; this increase was smaller than that observed after fasting alone (8- to 9-fold). Analysi s of cell lysates isolated from the periportal and perivenous region r evealed that the increase in CYP2E1 mRNA by fasting occurred in the pe rivenous region. Thus no evidence was obtained for an increased pretra nslational CYP2E1 gene expression as a consequence of the continuous p resence of ethanol at intoxicating levels for 3 days. CYP2E1 mRNA elev ation seems to be strongly associated with starvation while alcohol tr eatment increases the amount of enzyme, primarily by ligand-dependent stabilization of the synthesized protein. Our results indicate that tr anscriptional activation of CYP2E1 requires the long-term presence of highly intoxicating ethanol levels. It is conceivable that such activa tion occurs via indirect physiological responses related to those trig gered by starvation.