Miyata Masaaki, Takamatsu Yuki, Kuribayashi Hideaki, Yamazoe Yasushi
Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku, Sendai, 980-8578, Japan.
J Pharmacol Exp Ther. 2009 Dec;331(3):1079-85. doi: 10.1124/jpet.109.160093. Epub 2009 Sep 18.
Administration of the antibacterial drug ampicillin (ABPC) significantly increased hepatic bile acid concentrations. In the present study, we investigated the mechanisms for the elevation of bile acid levels in ABPC-treated mice. Hepatic microsomal cholesterol 7alpha-hydroxylation and CYP7A1 mRNA level were increased 2.0-fold in ABPC-treated mice despite higher bile acid levels in the liver and small intestinal lumen. A significant change in hepatic small heterodimer partner (SHP) mRNA level was not observed in ABPC-treated mice, whereas a marked decrease in ileal fibroblast growth factor 15 (FGF15) mRNA level was observed (3% of vehicle-treated mice). These phenomena were also observed in mice cotreated with bacitracin/streptomycin/neomycin, which are barely absorbed from the intestine. Primary bile acid contents in the small intestinal lumen were increased in ABPC-treated mice, whereas secondary bile acid, deoxycholic acid (DCA), contents were reduced to below detection limits (<0.01 micromol). In ABPC-treated mice, cotreatment with tauroDCA reversed reductions in ileal FGF15 mRNA level. Ileal SHP mRNA level was, however, not decreased in ABPC-treated mice. ABPC administration to farnesoid X receptor (Fxr)-null mice also decreased ileal FGF15 mRNA levels and secondary bile acid content in the small intestinal lumen. These results suggest that ABPC administration elevates hepatic primary bile acid synthesis, at least in part, through suppression of ileal FGF15 expression.
给予抗菌药物氨苄青霉素（ABPC）可显著提高肝脏胆汁酸浓度。在本研究中，我们探究了ABPC处理的小鼠胆汁酸水平升高的机制。尽管肝脏和小肠肠腔中的胆汁酸水平较高，但ABPC处理的小鼠肝脏微粒体胆固醇7α-羟化作用和CYP7A1 mRNA水平增加了2.0倍。在ABPC处理的小鼠中未观察到肝脏小异源二聚体伴侣（SHP）mRNA水平有显著变化，而回肠成纤维细胞生长因子15（FGF15）mRNA水平显著降低（为溶媒处理小鼠的3%）。在用杆菌肽/链霉素/新霉素共同处理的小鼠中也观察到了这些现象，这些药物几乎不被肠道吸收。ABPC处理的小鼠小肠肠腔中的初级胆汁酸含量增加，而次级胆汁酸脱氧胆酸（DCA）含量降至检测限以下（<0.01微摩尔）。在ABPC处理的小鼠中，与牛磺脱氧胆酸（tauroDCA）共同处理可逆转回肠FGF15 mRNA水平的降低。然而，ABPC处理的小鼠回肠SHP mRNA水平并未降低。对法尼醇X受体（Fxr）基因敲除小鼠给予ABPC也可降低回肠FGF15 mRNA水平和小肠肠腔中的次级胆汁酸含量。这些结果表明，给予ABPC至少部分通过抑制回肠FGF15表达来提高肝脏初级胆汁酸的合成。
