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Antibody-mediated Inhibition of Fibroblast Growth Factor-19 Results in Increased Bile Acids Synthesis and Ileal Malabsorption of Bile Acids in Cynomolgus Monkeys.
MedLine Citation:
PMID:  22268002     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
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 (BSEP, MRP2, MRP3) expression and reduced NTCP and OAT2 expression in liver tissues from treated monkeys and in primary hepatocytes. In addition, anti-FGF19 treatment increased solute transporter gene (IBABP, OST-α, OST-β) expression in ileal tissues from treated monkeys but not in Caco-2 cells. However, deoxycholic acid (DCA: a secondary bile acid) increased expression of FGF19 and these solute transporter genes in Caco-2 cells. GC-MS 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.
Authors:
Rama Pai; Dorothy French; Ning Ma; Kathy Hotzel; Emile Plise; Laurent Salphati; Kenneth D R Setchell; Joseph Ware; Veronique Lauriault; Schutt Leah; Dylan Hartley; Donna Dambach
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-1-19
Journal Detail:
Title:  Toxicological sciences : an official journal of the Society of Toxicology     Volume:  -     ISSN:  1096-0929     ISO Abbreviation:  -     Publication Date:  2012 Jan 
Date Detail:
Created Date:  2012-1-23     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9805461     Medline TA:  Toxicol Sci     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Department of Safety Assessment, Genentech Incorporated, South San Francisco, CA 94080.
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