人工感染猪链球菌对小鼠肝脏药物代谢酶的抑制作用

Inhibition of Hepatic Drug-Metabolizing Enzymes in Mice During Streptococcus suis Type 2 Infection

【目的】评价猪链球菌感染对小鼠肝脏药物代谢酶活性的影响。【方法】120只雄性ICR小鼠,随机分为对照组和2个感染组,后者分别人工感染猪链球菌2型强毒力株HA9801和弱毒力株SS2-H,于感染不同时间测定小鼠体内肝脏药物代谢酶活性的变化。【结果】感染HA9801菌株的小鼠,细胞色素P450(CytP450)、细胞色素b5(Cytb5)、NADP-细胞色素C还原酶(NCCD)活性从第3日开始极显著(P<0.01)或显著(P<0.05)降低,第10日时降至最低(NCCD于第5天时最低),第15日时活性有所增强,但仍显著低于对照组;红霉素-N-脱甲基酶(ERND)活性从第5日开始极显著地降低(P<0.01),变化趋势与CytP450、Cytb5相似;氨基比林-N-脱甲基酶(AND)活性虽有变化,但与对照组比较,差异不显著(P>0.05);苯胺-4-羟化酶(AH)活性在第10日时开始极显著地下降(P<0.01),第15日时稍有上升。感染SS2-H的小鼠,CytP450、Cytb5的活性从第5日开始显著降低(P<0.05),第10日降至最低;NCCD、ERND和AH活性第10日时显著降低(P<0.05),而AND活性在感染期间未发生显著变化(P>0.05)。HA9801感染组与SS2-H感染组小鼠的谷胱甘肽巯基转移酶(-GSH-S-T)活性从感染后第3日开始即显著(P<0.05)降低。HA9801感染组与SS2-H感染组比较,CytP450、Cytb5活性在感染前期均有极显著(第3日、第5日)差异(P<0.01),而在感染后期,差异不显著(P>0.05)。微粒体蛋白浓度各组差异不显著(P>0.05)。【结论】猪链球菌感染可调节小鼠肝脏药物代谢酶CytP450、Cytb5、NCCD、ERND、AH和GSH-S-T活性,故在感染期间选择药物进行治疗时,应制定合理的给药方案,避免药物毒性反应产生,加重病情。

[Objective] The effect of Streptococcus suis infection on both phase Ⅰ （oxidative） and phase Ⅱ （conjugative） microsomal enzyme activities was investigated in a well-characterized mice infection model. [ Method ] One hundred and twenty ICR mouse were used and divided randomly into infection groups （HA9801 group and SS2-H group） and negative control group. Each infected mouse was inoculated intraperioneally with one ml inoculum containing 1/2LD50 of each strain. One control group of mice was injected with one ml of sterile water. Body weight were weighed every day and the levels of liver microsomal protein, activities of cytP450, cytb5, NCCD, ERND, AND, AH and GSH-S-T were determined on 3, 5, 10, 15 days, respectively. [ Result ] Intraperitoneal injection of Streptococcus suis resulted in a time-dependent modulation of hepatic drug-metabolizing enzymes activities in mice. The activities of some drug-metabolizing enzymes of infected groups were significantly lowered compared with the negative control group during different infectious days, especially on 10 day post-infection, the lowest levels of cytP450, cytb5, NCCD, AH and ERND were achieved. While between the two infected groups, there was no obvious difference in the levels of all the enzymes tested except the levels of cytP450 and cyt b5 at the early stage. [ Conclusion ] The present study is the first to show that the infection by S. suis can decrease the activities of some hepatic drug-metabolizing enzymes in mice. If such a response also occurs in humans, this has the potential to produce serious complications with drug and endogenous substrate metabolism in patients with an infectious disease. The results also suggest that drugs with narrow therapeutic indices are dangerous during therapeutic schedule and should be administered with caution during infectious diseases caused by S. suis or other bacteria and viruses.