CHRONIC ALCOHOL INTAKE REDUCES RETINOIC ACID CONCENTRATION AND ENHANCES AP-1 (C-JUN AND C-FOS) EXPRESSION IN RAT-LIVER

Chronic ethanol intake may interfere with retinoid signal transduction by inhibiting retinoic acid synthesis and by enhancing activator prot ein-1 (AP-1) (c-Jun and c-Fos) expression, thereby contributing to mal ignant transformation. To determine the effect of ethanol on hepatic r etinoid levels, retinoic acid receptors (RARs) and AP-1 (c-Jun and c-F os) gene expression, chronic ethanol (36% of total calorie intake) pai r-feeding was conducted on rats for a 1-month period. Retinoic acid, r etinol, and retinyl ester concentrations in both liver and plasma were examined by using high-performance liquid chromatography (HPLC). Both retinoic acid receptor (alpha, beta, gamma) and AP-1 (c-Jun and c-Fos ) expression in the rat liver were examined by using Western blot anal ysis. Treatment with high-dose ethanol led to a significant reduction of retinoic acid concentration in both the liver and the plasma (11- a nd 8.5-fold reduction, respectively), as compared with animals pair-fe d an isocaloric control diet containing the same amount of vitamin A. Similar to the retinoic acid reductions, both retinol and retinyl palm itate levels in the livers of the alcohol-fed group decreased signific antly, but in smaller fold reduction (6.5- and 2.6-fold reduction, res pectively). Ethanol did not modulate the expression of RAR alpha, -bet a, and -gamma genes in the liver. However, chronic alcohol feeding enh anced AP-1 (c-Jun and c-Fos) expression by 7- to 8-fold, as compared w ith the control group. These data suggest that functional downregulati on of RARs by inhibiting biosynthesis of retinoic acid and up-regulati on of AP-1 gene expression may be important mechanisms for causing mal ignant transformation by ethanol.