Department of Safety Assessment, Genentech Incorporated, South San Francisco, California 94080, USA.
Toxicol Sci. 2012 Apr;126(2):446-56. doi: 10.1093/toxsci/kfs011. Epub 2012 Jan 19.
Fibroblast growth factor 19 (FGF19) represses cholesterol 7α-hydroxylase (Cyp7α1) and inhibits bile acid synthesis in vitro and in vivo. Previous studies have shown that anti-FGF19 antibody treatment reduces growth of colon tumor xenografts and prevents hepatocellular carcinomas in FGF19 transgenic mice and thus may be a useful cancer target. In a repeat dose safety study in cynomolgus monkeys, anti-FGF19 treatment (3-100 mg/kg) demonstrated dose-related liver toxicity accompanied by severe diarrhea and low food consumption. The mechanism of anti-FGF19 toxicity was investigated using in vitro and in vivo approaches. Our results show that anti-FGF19 antibody had no direct cytotoxic effect on monkey hepatocytes. Anti-FGF19 increased Cyp7α1, as expected, but also increased bile acid efflux transporter gene (bile salt export pump, multidrug resistant protein 2 [MRP2], and MRP3) expression and reduced sodium taurocholate cotransporting polypeptide and organic anion transporter 2 expression in liver tissues from treated monkeys and in primary hepatocytes. In addition, anti-FGF19 treatment increased solute transporter gene (ileal bile acid-binding protein, organic solute transporter α [OST-α], and OST-β) expression in ileal tissues from treated monkeys but not in Caco-2 cells. However, deoxycholic acid (a secondary bile acid) increased expression of FGF19 and these solute transporter genes in Caco-2 cells. Gas chromatography-mass spectrometry analysis of monkey feces showed an increase in total bile acids and cholic acid derivatives. These findings suggest that high doses of anti-FGF19 increase Cyp7α1 expression and bile acid synthesis and alter the expression of bile transporters in the liver resulting in enhanced bile acid efflux and reduced uptake. Increased bile acids alter expression of solute transporters in the ileum causing diarrhea and the enhanced enterohepatic recirculation of bile acids leading to liver toxicity.
成纤维细胞生长因子 19（FGF19）抑制胆固醇 7α-羟化酶（Cyp7α1）并在体外和体内抑制胆汁酸合成。先前的研究表明，抗 FGF19 抗体治疗可减少结肠肿瘤异种移植物的生长，并可预防 FGF19 转基因小鼠的肝细胞癌，因此可能是一种有用的癌症靶点。在恒河猴重复剂量安全性研究中，抗 FGF19 治疗（3-100mg/kg）显示出剂量相关性肝毒性，伴有严重腹泻和食物摄入减少。使用体外和体内方法研究了抗 FGF19 毒性的机制。我们的结果表明，抗 FGF19 抗体对猴肝细胞没有直接细胞毒性作用。抗 FGF19 增加了 Cyp7α1，这是预期的，但也增加了胆汁酸外排转运蛋白基因（胆汁盐输出泵、多药耐药蛋白 2 [MRP2]和 MRP3）的表达，并降低了钠牛磺胆酸盐共转运蛋白和有机阴离子转运蛋白 2 的表达在治疗猴的肝组织和原代肝细胞中。此外，抗 FGF19 治疗增加了治疗猴回肠组织中的溶质转运蛋白基因（回肠胆汁酸结合蛋白、有机溶质转运蛋白α[OST-α]和 OST-β）的表达，但不在 Caco-2 细胞中。然而，脱氧胆酸（次级胆汁酸）增加了 Caco-2 细胞中 FGF19 和这些溶质转运蛋白基因的表达。猴粪便的气相色谱-质谱分析显示总胆汁酸和胆酸衍生物增加。这些发现表明，高剂量的抗 FGF19 增加 Cyp7α1 的表达和胆汁酸合成，并改变肝脏中胆汁转运蛋白的表达，导致胆汁酸外排增加和摄取减少。增加的胆汁酸改变回肠中溶质转运蛋白的表达，导致腹泻，并增强胆汁酸的肠肝再循环，导致肝毒性。
