肝纤维化状态下小肠药物代谢功能的改变

目的　探讨肝纤维化时小肠药物代谢功能的变化 ,为合理用药提供依据。方法　在大鼠肝纤维化模型上 ,测定小肠粘膜上皮细胞药物代谢酶、抗氧化酶及膜流动性变化 ,并与急性肝损伤、慢性肝硬化大鼠小肠相关指标进行比较。结果　与正常对照组相比 ,肝纤维化大鼠小肠粘膜上皮细胞药物代谢Ⅰ相酶红霉素N 脱甲基酶 (CYP3A)、7 乙氧异口恶唑O 脱乙基酶 (CYP1A1)和苯胺羟化酶 (CYP2E1)活性分别增加 2 .2 ,0 .6和 0 .3倍 ,而Ⅱ相酶葡糖醛酸转移酶 (UDPGT)和α 、π 谷胱甘肽S 转移酶 (GST)活性则分别减少 15 % ,4 3%和 5 7% ,同时膜脂质过氧化产物增加 ,抗氧化酶活性减弱 ,膜流动性降低。急性肝损伤时 ,上述指标无明显变化 ,而肝硬化时上述指标与肝纤维化组变化一致 ,并进一步增强。结论肝纤维化可影响小肠粘膜上皮细胞药物代谢功能 ,使Ⅰ相氧化功能增强 ,Ⅱ相结合反应减弱。小肠抗氧化功能降低可能与Ⅰ相氧化代谢增强有关。

Changes of drug-metabolizing function of small intestinal mucosal epithelial cells in hepatic fibrosis rats

AIM To provide experimental data for rational design of therapeutic scheme. METHODS Drug-metabolizing enzymes, antioxidative enzymes and membrane fluidity of small intestinal mucosal epithelial cells were measured in hepatic fibrosis rats and compared with those in acute hepatic injury and hepatic cirrhosis rats. RESULTS In hepatic fibrosis, the activities of phaseⅠ enzymes-erythromycin N-demethylase (CYP3A), 7-ethoxyresorufindeethylase(CYP1A1) and aniline hydroxylase (CYP2E1) of small intestinal mucosal epithelial cells enhanced 2.2-, 0.6- and 0.3-times respectively, in comparison with control group, however, the activities of phaseⅡ enzymes-uridine diphosphateglucuronate transferase, α-, π-glutathione S-transferase decreased 15%, 43% and 57%, respectively. Meanwhile, the content of membrane malondialdehyde increased, and the activities of antioxidative enzymes and membrane fluidity decreased. In acute hepatic injury, the above indexes showed no obvious changes, however in hepatic cirrhosis, the changes were consistent with those in hepatic fibrosis but increased more. CONCLUSION Hepatic fibrosis could influence drug metabolism of small intestinal mucosal epithelial cells. PhaseⅠ oxidations increased but phaseⅡ conjugations decreased. The changes of antioxidative function may be associated with the increase of phaseⅠ oxidations.