Ishii Makoto, Toda Takahiro, Ikarashi Nobutomo, Ochiai Wataru, Sugiyama Kiyoshi
Department of Clinical Pharmacokinetics, Hoshi University, Tokyo, Japan.
Yakugaku Zasshi. 2012;132(3):301-10. doi: 10.1248/yakushi.132.301.
Living organisms eliminate foreign low-antigenic substances, such as drugs and environmental pollutants, by detoxification mediated by metabolizing cytochrome P450 (CYP). We have examined the possible regulation of CYP expression by enteric bacteria. Cyp mRNA expression levels, Cyp3a protein expression level, and the activity of Cyp3a in hepatic microsomal fractions were compared in germ-free (GF) and specific pathogen-free (SPF) mice. We evaluated hepatic Cyp3a11 mRNA expression levels and Cyp3a metabolic activity in GF and SPF mice after five days of antibiotic administration. The fecal levels of lithocholic acid (LCA)-producing bacteria and hepatic taurolithocholic acid (TLCA) were also measured. Cyp mRNA expression levels, Cyp3a protein expression level, and the activity of Cyp3a in SPF mice were higher than those in GF mice, indicating that enteric bacteria increases hepatic Cyp3a expression. The effects of enteric bacteria-reducing antibiotics on Cyp3a expression were examined. We observed that decreasing enteric bacteria with antibiotics in SPF mice caused a significant decrease in the hepatic Cyp3a11 mRNA expression, TLCA, and fecal LCA-producing bacteria compared to the group that did not receive antibiotics. No change in Cyp3a11 expression was observed in GF mice that were treated with antibiotics. Administration of LCA to GF mice showed an increase in Cyp3a11 expression similar to that of SPF mice. The enzymes of the enteric bacteria are believed to metabolize and detoxify drugs by either reduction or hydrolysis. The results of this study indicate that changes in enteric bacteria may alter the expression and activity of hepatic drug metabolizing enzymes and pharmacokinetics. Therefore, enteric bacteria should be closely monitored to ensure the safe use of drugs.
生物通过细胞色素P450（CYP）介导的代谢解毒作用来清除外来的低抗原性物质，如药物和环境污染物。我们研究了肠道细菌对CYP表达的可能调节作用。比较了无菌（GF）小鼠和无特定病原体（SPF）小鼠肝脏微粒体组分中Cyp mRNA表达水平、Cyp3a蛋白表达水平以及Cyp3a的活性。我们评估了抗生素给药五天后GF和SPF小鼠肝脏中Cyp3a11 mRNA表达水平和Cyp3a代谢活性。还测量了产生石胆酸（LCA）的细菌的粪便水平和肝脏牛磺石胆酸（TLCA）。SPF小鼠中的Cyp mRNA表达水平、Cyp3a蛋白表达水平和Cyp3a的活性高于GF小鼠，表明肠道细菌可增加肝脏Cyp3a表达。研究了减少肠道细菌的抗生素对Cyp3a表达的影响。我们观察到，与未接受抗生素的组相比，用抗生素减少SPF小鼠肠道细菌会导致肝脏Cyp3a11 mRNA表达、TLCA和粪便中产生LCA的细菌显著减少。在用抗生素治疗的GF小鼠中未观察到Cyp3a11表达的变化。给GF小鼠施用LCA后，Cyp3a11表达增加，与SPF小鼠相似。据信肠道细菌的酶可通过还原或水解作用代谢和解毒药物。本研究结果表明，肠道细菌的变化可能会改变肝脏药物代谢酶的表达和活性以及药代动力学。因此，应密切监测肠道细菌以确保药物的安全使用。
