College of Pharmacy, Yeungnam University, Gyeongsan, 712-749, Korea.
Arch Pharm Res. 2012 Mar;35(4):733-8. doi: 10.1007/s12272-012-0418-y. Epub 2012 May 3.
Possible role of metabolism by the intestinal bacteria in geniposide-induced cytotoxicity was investigated in human hepatoma HepG2 cells. Initially, toxic effects of geniposide and its metabolite genipin were compared. Genipin, a deglycosylated form of geniposide, was cytotoxic at the concentrations that geniposide was not. As metabolic activation systems for geniposide, human intestinal bacterial cultures, fecal preparation (fecalase) and intestinal microbial enzyme mix were employed in the present study. When geniposide was incubated with human intestinal bacteria, either Bifidobacterium longum HY8001 or Bacteroides fragilis, for 24 h, the cultured media caused cytotoxicity in HepG2 cells. Fecalase and intestinal enzyme mix were also effective to metabolically activate geniposide to its cytotoxic metabolite. The present results indicated that genipin, a metabolite of geniposide, might be more toxic than geniposide, and that intestinal bacteria might have a role in biotransformation of geniposide to its toxic metabolite. In addition, among three activation systems tested, intestinal microbial enzyme mix would be convenient to use in detecting toxicants requiring metabolic activation by intestinal bacteria.
本研究旨在探讨肠道细菌代谢物在栀子苷诱导的细胞毒性中的可能作用。首先，比较了栀子苷及其代谢产物京尼平苷的毒性作用。京尼平苷是栀子苷的去糖基化形式，在栀子苷没有毒性的浓度下具有细胞毒性。本研究采用人肠道细菌培养物、粪便制剂（粪便酶）和肠道微生物酶混合物作为栀子苷的代谢激活系统。当栀子苷与人肠道细菌（长双歧杆菌 HY8001 或脆弱拟杆菌）孵育 24 小时时，培养的培养基会导致 HepG2 细胞的细胞毒性。粪便酶和肠道酶混合物也能有效地将栀子苷代谢为其具有细胞毒性的代谢物。本研究结果表明，京尼平苷，栀子苷的代谢产物，可能比栀子苷毒性更大，肠道细菌可能在栀子苷向其毒性代谢物的生物转化中起作用。此外，在测试的三种激活系统中，肠道微生物酶混合物在检测需要肠道细菌代谢激活的毒物时更为方便。
