Prevention of fibrosis reduces enzyme-altered lesions in the rat liver.
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.
Sakaida
I
I
First Department of Internal Medicine, School of Medicine, Yamaguchi University, Japan.
Kubota
M
M
Kayano
K
K
Takenaka
K
K
Mori
K
K
Okita
K
K
D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D002796:Choline Deficiency / Q000378:metabolism; D004032:Diet; D004195:Disease Models, Animal; D005982:Glutathione Transferase / Q000378:metabolism; D006909:Hydroxyproline / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008106:Liver Cirrhosis, Experimental / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control*; D008114:Liver Neoplasms, Experimental / Q000201:enzymology* / Q000209:etiology / Q000517:prevention & control*; D008297:Male; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors; D011355:Prodrugs / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar
D000596:Amino Acids; D011355:Prodrugs; D011725:Pyridines; C074630:lufironil; D011393:Procollagen-Proline Dioxygenase; D005982:Glutathione Transferase; D006909:Hydroxyproline