异补骨脂素不同时间给药对大鼠肝脏功能和转运体的影响
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摘要
目的探讨补骨脂活性成分异补骨脂素不同时间灌胃给药对大鼠肝脏功能和胆汁酸转运体的影响。方法 SD大鼠随机分为对照组、异补骨脂素60 mg·kg~(-1)灌胃给药1 d组、3 d组以及7 d组。实验结束后,检测大鼠的体质量和肝重;试剂盒检测大鼠血清中ALT、AST、ALP、TBA、TC、TG、TBIL的含量;real-time PCR法检测大鼠肝脏组织中胆汁酸转运体BSEP、NTCP、MRP2、MRP4、MDR1、ABCG5、ABCG8、OSTα的水平。结果与对照组相比,异补骨脂素能明显增加肝脏的重量,不同给药时间均能引起肝脏系数的增加;异补骨脂素给药后,大鼠血清中ALT、 AST、TBA、TG、TBIL的含量明显增加,ALP没有明显变化,TC明显降低,且AST的水平在异补骨脂素灌胃给药1 d之后即有明显升高;异补骨脂素灌胃给药后,肝脏中BSEP、NTCP、MRP2、MDR1、ABCG5、ABCG8、OSTαmRNA的水平明显下降,MRP4 mRNA的水平没有明显变化。结论异补骨脂素灌胃给药1～3 d即造成肝脏的损伤作用,其作用机制可能与干扰胆汁酸转运体有关。
Aim To investigate the effect of isopsoralen, the active ingredient of Psoralea corylifolia, on rat liver and bile acid transporters after oral administration for different time. Methods Rats were randomly divided into four groups: the control group and the groups treated with 60 mg·kg~(-1) isopsoralen for 1, 3 or 7 days. After the experiment, the body weight and liver weight were measured. The levels of ALT, AST, ALP, TBA, TC, TG and TBIL in rat serum were examined by different kits. The mRNA levels of BSEP, NTCP, MRP2, MRP4, MDR1, ABCG5, ABCG8 and OSTα in rat liver were detected by real-time PCR. Results Compared with control group, isopsoralen could induce the increase of liver weight and liver/body weight ratio. The levels of ALT, AST, TBA, TG and TBIL significantly increased after administration of isopsoralen. The content of ALP did not change significantly and the content of TC decreased remarkably. Furthermore, the level of AST significantly increased after one day of isopsoralen administration. After treatment with isopsoralen, the mRNA levels of BSEP, NTCP, MRP2, MDR1, ABCG5, ABCG8 and OSTα were distinctly reduced. The mRNA levels of MRP4 showed no significant difference. Conclusions The administration of isopsoralen for 1 to 3 days may cause obvious liver injury. The mechanism underlying isopsoralen-induced injury may be associated with the interference of bile acid transporters.
Aim To investigate the effect of isopsoralen, the active ingredient of Psoralea corylifolia, on rat liver and bile acid transporters after oral administration for different time. Methods Rats were randomly divided into four groups: the control group and the groups treated with 60 mg·kg~(-1) isopsoralen for 1, 3 or 7 days. After the experiment, the body weight and liver weight were measured. The levels of ALT, AST, ALP, TBA, TC, TG and TBIL in rat serum were examined by different kits. The mRNA levels of BSEP, NTCP, MRP2, MRP4, MDR1, ABCG5, ABCG8 and OSTα in rat liver were detected by real-time PCR. Results Compared with control group, isopsoralen could induce the increase of liver weight and liver/body weight ratio. The levels of ALT, AST, TBA, TG and TBIL significantly increased after administration of isopsoralen. The content of ALP did not change significantly and the content of TC decreased remarkably. Furthermore, the level of AST significantly increased after one day of isopsoralen administration. After treatment with isopsoralen, the mRNA levels of BSEP, NTCP, MRP2, MDR1, ABCG5, ABCG8 and OSTα were distinctly reduced. The mRNA levels of MRP4 showed no significant difference. Conclusions The administration of isopsoralen for 1 to 3 days may cause obvious liver injury. The mechanism underlying isopsoralen-induced injury may be associated with the interference of bile acid transporters.
引文
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[8] 宋蕾, 毕亚男, 袁晓美, 等. 异补骨脂素腹腔注射9 d所致的C57小鼠肝损害[J]. 毒理学杂志, 2018,32(1):21-4. Song L, Bi Y N,Yuan X M, et al. Study on the influence of isopsoralen on C57 mice liver injury after intraperitoneal injection for 9 days[J]. J Toxicol, 2018,32(1):21-4.
[9] Lee S J, Nam K W, Mar W. Induction of quinone reductase activity by psoralidin isolated from Psoralea corylifolia in mouse hepa 1c1c7 cells[J]. Arch Pharm Res, 2009,32(7):1061-5.
[10] Yadava R N, Verma V. A new biologically active flavonol glycoside from Psoralea corylifolia (Linn.) [J]. J Asian Nat Prod Res,2005,7(4):671-5.
[11] Chen Y, Cheung Y T, Kong L D, et al. Transcriptional regulation of corticotrophin releasing factor gene by furocoumarins isolated from seeds of Psoralea corylifolia[J]. Life Sci, 2008,82(21-22):1117-21.
[12] Lim S H, Ha T Y, Kim S R, et al. Ethanol extract of Psoralea corylifolia L. and its main constituent, bakuchiol, reduce bone loss in ovariectomised Sprague-Dawley rats[J]. Br J Nutr, 2009,101(7):1031-9.
[13] 韩平, 田德安. 肝内胆汁淤积发病机制及药物治疗新进展[J]. 胃肠病学和肝病学杂志, 2016,25(5):584-8. Han P, Tian D A. New progress of pathogenesis and therapeutic agents of hepatic cholestasis[J]. Chin J Gastroenterol Hepatol, 2016,25(5):584-8.
[14] Palmeira C M, Rolo A P. Mitochondrially-mediated toxicity of bile acids[J]. Toxicology,2004,203(1-3):1-15.
[15] Geier A, Dietrich C G, Gerloff T, et al. Regulation of basolateral organic anion transporters in ethinylestradiol-induced cholestasis in the rat[J]. Biochim Biophys Acta, 2003,1609(1):87-94.
[16] 陈攀, 李晶洁, 陈杰. 以核受体为靶标的胆汁淤积治疗药物研究进展[J]. 中国药理学通报,2015,31(9):1195-8. Chen P, Li J J, Chen J. Nuclear receptor as drug targets in cholestasis[J]. Chin Pharmacol Bull, 2015,31(9):1195-8.
[2] Cheung W I, Tse M L, Ngan T, et al. Liver injury associated with the use of Fructus Psoraleae (Bol-gol-zhee or Bu-gu-zhi) and its related proprietary medicine[J]. Clin Toxicol (Phila), 2009,47(7):683-5.
[3] Nam S W, Baek J T, Lee D S, et al. A case of acute cholestatic hepatitis associated with the seeds of Psoralea corylifolia (Boh-Gol-Zhee) [J]. Clin Toxicol (Phila), 2005,43(6):589-91.
[4] 唐进法, 王晓艳, 杨伟, 等. 基于统计建模的壮骨关节丸诱发特异质肝损伤相关易感性细胞因子分析[J].药学学报,2018,53(4):574-84. Tang J F, Wang X Y, Yang W, et al. Cytokine analysis of Zhuangguguanjie wan-induced idiosyncratic liver injury based on mathematical modeling[J]. Acta Pharm Sin, 2018, 53(4): 574-84.
[5] 周昆, 代志, 柳占彪, 等. 补骨脂水提物引起的大鼠肝损害[J].天津中医药大学学报, 2013,32(4):221-4. Zhou K, Dai Z, Liu Z B, et al. Aqueous extract of Psoralea corylifolia induced liver injury in rats[J]. J Tianjin Univ Tradit Chin Med, 2013,32(4):221-4.
[6] 张玥, 毕亚男, 袁晓美, 等. 基于靶器官的补骨脂肝毒性成分探讨[J]. 时珍国医国药, 2017,28(8):1844-7. Zhang Y, Bi Y N, Yuan X M, et al. Study on the hepatotoxicity components of Psoralea corylifolia based on target organs [J]. Lishizhen Med Mater Med Res, 2017,28(8):1844-7.
[7] 周昆, 毕亚男, 史红. 异补骨脂素抑制MRP2、MRP3所致的HepG2细胞内胆汁酸蓄积和毒性[J]. 中国药理学通报, 2015,31(8):1112-6. Zhou K, Bi Y N, Shi H. Psoralen induced bile acid accumulation and cytotoxicity by inhibiting MRP2 and MRP3 in HepG2 cells[J]. Chin Pharmacol Bull, 2015,31(8):1112-6.
[8] 宋蕾, 毕亚男, 袁晓美, 等. 异补骨脂素腹腔注射9 d所致的C57小鼠肝损害[J]. 毒理学杂志, 2018,32(1):21-4. Song L, Bi Y N,Yuan X M, et al. Study on the influence of isopsoralen on C57 mice liver injury after intraperitoneal injection for 9 days[J]. J Toxicol, 2018,32(1):21-4.
[9] Lee S J, Nam K W, Mar W. Induction of quinone reductase activity by psoralidin isolated from Psoralea corylifolia in mouse hepa 1c1c7 cells[J]. Arch Pharm Res, 2009,32(7):1061-5.
[10] Yadava R N, Verma V. A new biologically active flavonol glycoside from Psoralea corylifolia (Linn.) [J]. J Asian Nat Prod Res,2005,7(4):671-5.
[11] Chen Y, Cheung Y T, Kong L D, et al. Transcriptional regulation of corticotrophin releasing factor gene by furocoumarins isolated from seeds of Psoralea corylifolia[J]. Life Sci, 2008,82(21-22):1117-21.
[12] Lim S H, Ha T Y, Kim S R, et al. Ethanol extract of Psoralea corylifolia L. and its main constituent, bakuchiol, reduce bone loss in ovariectomised Sprague-Dawley rats[J]. Br J Nutr, 2009,101(7):1031-9.
[13] 韩平, 田德安. 肝内胆汁淤积发病机制及药物治疗新进展[J]. 胃肠病学和肝病学杂志, 2016,25(5):584-8. Han P, Tian D A. New progress of pathogenesis and therapeutic agents of hepatic cholestasis[J]. Chin J Gastroenterol Hepatol, 2016,25(5):584-8.
[14] Palmeira C M, Rolo A P. Mitochondrially-mediated toxicity of bile acids[J]. Toxicology,2004,203(1-3):1-15.
[15] Geier A, Dietrich C G, Gerloff T, et al. Regulation of basolateral organic anion transporters in ethinylestradiol-induced cholestasis in the rat[J]. Biochim Biophys Acta, 2003,1609(1):87-94.
[16] 陈攀, 李晶洁, 陈杰. 以核受体为靶标的胆汁淤积治疗药物研究进展[J]. 中国药理学通报,2015,31(9):1195-8. Chen P, Li J J, Chen J. Nuclear receptor as drug targets in cholestasis[J]. Chin Pharmacol Bull, 2015,31(9):1195-8.