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.
First Department of Internal Medicine, School of Medicine, Yamaguchi University, Japan.
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Sakaida
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Kubota
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Kayano
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Takenaka
K
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Mori
K
K
Okita
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