CYP3A4在黄曲霉毒素B1诱发大鼠肝癌过程中的表达及意义

探讨CYP3A4在黄曲霉毒素B1（AFB1）实验诱发大鼠肝癌过程中的活性变化及其在肝癌发生过程中的意义。方法:雄性、4周龄、Wistar大鼠随机分为AFB1组和对照组；AFB1组腹腔注射AFB1，对照组则给与溶媒二甲基亚砜。在诱发肝癌过程中，分别于第13、23、33、43、53、63周对大鼠进行肝活检；实验至第73周处死全部动物取肝组织；利用大鼠肝组织微粒体混合酶体外代谢体系，采用荧光分光光度定量法动态检测肝标本中CYP3A4酶活性。结果:AFB1组肝细胞癌发生率为58.8%（10/17）；对照组肝细胞癌发生率为0（0/16），两组间肝癌发生率比较，AFB1组显著高于对照组（P=0.001）。两组大鼠肝组织代谢酶CYP3A4活性都有不同程度的变化。肝组织CYP3A4活性从13 w开始逐渐升高，至23 w达顶峰，然后逐渐降低，到43 w又升高，出现双波峰变化；从13 w至53 w不同时段AFB1组肝组织CYP3A4活性显著低于对照组（P<0.01）。但是至63 w时AFB1组肝组织CYP3A4活性基本接近对照组（P=0.5086）。结论:CYP3A4活性在AFB1诱癌过程中受到抑制，可能是由于癌变早期的细胞减少对致癌物质的活化有关；CYP3A4活性在AFB1诱癌过程中的表达起伏变化，是由于基因多态性较大程度上影响蛋白表达水平的结果。 

Activity and Significance of CYP3A4 in Aflatoxin B1-induced Hepatocarcinogenesis in Wistar Rats

To investigate the change in CYP3A4 activity and its significance in hepatocarcinogenesis induced by aflatoxin B1 ( AFB1 ) in rats. Methods: Four-week old male Wistar rats were randomly divided into AFB1 and control groups. Rats in the AFB1 groups were intraperitoneally injected with AFB1 and dimethyl sulfoxide. During hepatocarcinogenesis, liver biopsies were performed on all animals on the 13th, 23rd, 33rd, 43rd, 53rd, and 63rd week of the experiment. The animals were sacrificed on the 73rd week and liver tissues were collected. Using the hepatic microsomal mixed-function oxidase enzyme system, the CYP3A4 activity was dynamically examined in liver samples via quantitative fluorescence spectrophotometry. Results: The hepatocellular carcinoma incidence in the AFB1 group ( 58.8%, 10/17 ) was significantly higher than in the control group ( 0.0%, 0/16 ), with P = 0.001. Both groups exhibited different levels of changes in CYP3A4 activity. The CYP3A4 activity in both groups? gradually increased from the 13th week of the experiment, with a peak value on the 23rd week. The activity then gradually decreased, and again increased on the 43rd week, forming double peaks. The CYP3A4 activities in the AFB1 group significantly decreased during the 13rd and 53rd weeks compared with those of the control group ( P = 0.000 ). The level of CYP3A4 activity in the AFB1 group was close but not statistically significant to that of the control group on the 63rd week ( P = 0.5086 ). Conclusion: The CYP3A4 activity was inhibited in rats during hepatocarcinogenesis. This inhibition may be due to the decreased carcinogen activation in cells and the change in protein expression caused by genetic polymorphisms.