Prevention of fibrosis reduces enzyme-altered lesions in the rat liver.

Abstract

A choline-deficient L-amino acid-defined (CDAA) diet led to the development of liver cirrhosis in 100% of male Wistar rats after 16 weeks. In contrast, an ordinary (semipurified) choline-deficient (CD) diet led to the development of liver cirrhosis in only 33.3%. After 16 weeks, the liver hydroxyproline content, which reflects the amount of collagen, increased to a level more than four times higher in rats fed a CDAA diet than in rats fed a choline-supplemented L-amino acid-defined (CSAA) diet. Concurrent administration of a prolyl 4-hydroxylase inhibitor, 2,4-pyridine dicarboxylic acid bis(2-methoxyethyl amide) (HOE 077), to rats fed a CDAA diet reduced this increase in liver hydroxyproline content in a dose-dependent manner for doses up to 200 p.p.m. Microscopically, reduction in the hydroxyproline content of the liver resulted in a reduced number of pseudolobuli and thinner fibrous septa. HOE 077 showed no effect on liver hydroxyproline content in rats fed a CSAA diet. The administration of a CDAA diet for 16 weeks led to a substantial induction of GSTP-positive lesions in the liver. The concurrent administration of HOE 077 reduced the number, average diameter and percent area of GSTP-positive lesions in a dose-dependent manner, in parallel with the reduction in hydroxyproline content. These data suggest that inhibition of fibrosis may limit the development of subsequent neoplasms.