Wang X D, Liu C, Chung J, Stickel F, Seitz H K, Russell R M
USDA JM Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111, USA.
Hepatology. 1998 Sep;28(3):744-50. doi: 10.1002/hep.510280321.
Chronic ethanol intake may interfere with retinoid signal transduction by inhibiting retinoic acid synthesis and by enhancing activator protein-1 (AP-1) (c-Jun and c-Fos) expression, thereby contributing to malignant transformation. To determine the effect of ethanol on hepatic retinoid levels, retinoic acid receptors (RARs) and AP-1 (c-Jun and c-Fos) gene expression, chronic ethanol (36% of total calorie intake) pair-feeding was conducted on rats for a 1-month period. Retinoic acid, retinol, 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 analysis. Treatment with high-dose ethanol led to a significant reduction of retinoic acid concentration in both the liver and the plasma (11- and 8.5-fold reduction, respectively), as compared with animals pair-fed an isocaloric control diet containing the same amount of vitamin A. Similar to the retinoic acid reductions, both retinol and retinyl palmitate levels in the livers of the alcohol-fed group decreased significantly, but in smaller fold reduction (6.5- and 2.6-fold reduction, respectively). Ethanol did not modulate the expression of RARalpha, -beta, and -gamma genes in the liver. However, chronic alcohol feeding enhanced AP-1 (c-Jun and c-Fos) expression by 7- to 8-fold, as compared with the control group. These data suggest that functional downregulation of RARs by inhibiting biosynthesis of retinoic acid and up-regulation of AP-1 gene expression may be important mechanisms for causing malignant transformation by ethanol.
长期摄入乙醇可能通过抑制视黄酸合成以及增强激活蛋白-1（AP-1，即c-Jun和c-Fos）的表达来干扰类视黄醇信号转导，从而促进恶性转化。为了确定乙醇对肝脏类视黄醇水平、视黄酸受体（RARs）和AP-1（c-Jun和c-Fos）基因表达的影响，对大鼠进行了为期1个月的长期乙醇（占总热量摄入的36%）配对喂养实验。通过高效液相色谱法（HPLC）检测肝脏和血浆中的视黄酸、视黄醇和视黄酯浓度。采用蛋白质免疫印迹分析检测大鼠肝脏中视黄酸受体（α、β、γ）和AP-1（c-Jun和c-Fos）的表达。与喂食等热量对照饮食（含等量维生素A）的配对喂养动物相比，高剂量乙醇处理导致肝脏和血浆中的视黄酸浓度显著降低（分别降低了11倍和8.5倍）。与视黄酸的降低情况类似，乙醇喂养组肝脏中的视黄醇和棕榈酸视黄酯水平也显著下降，但降低倍数较小（分别降低了6.5倍和2.6倍）。乙醇并未调节肝脏中RARα、β和γ基因的表达。然而，与对照组相比，长期酒精喂养使AP-1（c-Jun和c-Fos）的表达增强了7至8倍。这些数据表明，通过抑制视黄酸生物合成导致RARs功能下调以及AP-1基因表达上调可能是乙醇导致恶性转化的重要机制。
