The prolyl 4-hydroxylase inhibitor HOE 077 prevents activation of Ito cells, reducing procollagen gene expression in rat liver fibrosis induced by choline-deficient L-amino acid-defined diet

✍ Scribed by I Sakaida; Y Matsumura; M Kubota; K Kayano; K Takenaka; K Okita

• Publisher: John Wiley and Sons
• Year: 1996
• Tongue: English
• Weight: 723 KB
• Volume: 23
• Category: Article
• ISSN: 0270-9139
• DOI: 10.1002/hep.510230416

✦ Synopsis

No effective therapy has yet developed for liver fibro-Among the different causes of liver cirrhosis, one sis by directory inhibiting the accumulation of extracelcommon feature is an increased deposition of extracellular matrix. The effect of a newly synthesized prolyl lular matrix, which consists mainly of collagen, in the 4-hydroxylase (PH) inhibitor, HOE 077 (pyridine-2,4-diliver, 1 leading to portal hypertension, esophageal varicarboxylic-di(2-methoxyethyl)amide), was examined usces, and liver failure.

ing the model of choline-deficient L-amino acid (CDAA)

A key enzyme in collagen synthesis is prolyl 4-hydefined diet-induced liver fibrosis in 16-week-old male droxylase, 2,3 which catalyzes the hydroxylation of pep-Wistar rats. HOE 077 at doses up to 200 ppm prevented tide-bound proline residues to 4-hydroxyproline. Hyfibrosis in a dose-dependent manner, as indicated by redrogen bonds, including those of hydroxyl groups, play duced hydroxyproline content in liver as well as inhibia crucial role in stabilizing the triple helix of collagetion of increased serum fibrotic markers (PIIIP, 7S, hyaluronic acid). HOE 077 at 200 ppm reduced expression of nous proteins. Newly synthesized procollagen motype III procollagen a 1 messenger RNA (mRNA) in the leclues that have not undergone hydroxylation are unliver, with a good correlation with serum PIIIP and hyable to form a stable triple helix, resulting in their droxyproline content of the liver. Histologically, HOE rapid degradation at physiological temperature. Thus, 077 at 200 ppm also reduced proliferation of myofiprolyl 4-hydroxylase is an excellent target enzyme in broblastlike cells (activated Ito cells). These results indiefforts to prevent fibrogenesis.

cate that a PH inhibitor can prevent fibrosis by inhib-

The new prolyl 4-hydroxylase inhibitor, HOE 077 iting not only the hydroxylation of proline but also the (Hoechst Pharmaceutical Co., Frankfurt, Germany), is activation of Ito cells, which are considered the main a proinhibitor that is absorbed well from the gastroincollagen-producing cells, resulting in reduced exprestestinal tract, taken up by the liver, and metabolized sion of procollagen mRNA. (HEPATOLOGY 1996;23:755-763.) in hepatocytes to a competitive inhibitor of prolyl 4hydroxylase. 4,5 In the present study, we induced the development of Liver cirrhosis is very common disease in Japan as liver cirrhosis in male Wistar rats by administering a well as in other countries and results from chronic hepcholine-deficient L-amino acid (CDAA) defined diet 6,7 atitis (type B or type C), ethanol abuse, or other condiinstead of a semipurified choline-deficient diet. 8,9 The tions. Interferon alfa and beta have been studied as replacement of protein with same equivalent of L- possible therapeutic agents for the eradication of virus amino acids (a CDAA diet) had a more necrogenic effect in patients with chronic viral hepatitis resulting in the caused by a lack of oligopeptides and antioxidant minprevention of liver fibrosis. However, the results of erals resulting in more active fibrosis compared with these studies have been generally unsatisfactory.

a semipurified choline-deficient (CD) diet. 7 Using this model, we investigated the mechanism and effects of HOE 077 on the extent of liver fibrosis and on liver Abbreviations: CDAA, choline-deficient L-amino acid; mRNA, messenger function. Our results showed that HOE 077 prevented RNA; CSAA, choline-supplemented L-amino acid; ALT, alanine aminotransferase; AST, aspartate aminotransferase; cDNA, complementary DNA.

liver cirrhosis and improved liver function by inhibiting

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