Fujiwara K, Ogata I, Ohta Y, Hayashi S, Mishiro S, Takatsuki K, Sato Y, Yamada S, Hirata K, Oka H
First Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
Hepatology. 1988 Jul-Aug;8(4):804-7. doi: 10.1002/hep.1840080418.
Hepatic fibrosis was induced in rats by repeated i.p. injections of pig serum. The hepatic hydroxyproline content increased to 2.1 times the normal control level at 6 weeks and to 3.2 times at 10 weeks. When P-1894B, an inhibitor of prolyl hydroxylase, was administered, there was a dose-dependent inhibition of the increase to nearly normal control levels at 6 and 10 weeks. There was also by histology a dose-dependent reduction in the degree of hepatic fibrosis. Hepatocellular damage was minimal and its extent did not vary with the degree of fibrosis or the treatment. P-1894B dose dependently reduced the hydroxylation of peptidyl proline in the fibrotic liver. These data suggest that P-1894B inhibited hepatic fibrogenesis by direct action on collagen but not by protection against hepatocellular damage leading to collagen formation. A prolyl hydroxylase inhibitor may be a candidate for use in treatment of hepatic fibrosis.
通过腹腔内反复注射猪血清在大鼠中诱导肝纤维化。肝羟脯氨酸含量在6周时增加至正常对照水平的2.1倍，在10周时增加至3.2倍。当给予脯氨酰羟化酶抑制剂P-1894B时，在6周和10周时出现剂量依赖性抑制，使其增加几乎恢复至正常对照水平。组织学检查也显示肝纤维化程度呈剂量依赖性降低。肝细胞损伤最小，其程度不随纤维化程度或治疗而变化。P-1894B剂量依赖性地降低纤维化肝脏中肽基脯氨酸的羟化。这些数据表明，P-1894B通过直接作用于胶原蛋白来抑制肝纤维化，而不是通过防止导致胶原蛋白形成的肝细胞损伤来发挥作用。脯氨酰羟化酶抑制剂可能是用于治疗肝纤维化的候选药物。
