Selective inhibition of hepatic collagen accumulation in experimental liver fibrosis in rats by a new prolyl 4-hydroxylase inhibitor

Abstract

Fibrosis and cirrhosis of the liver are often the result of chronic liver damage by a variety of different agents. Pathological accumulation of collagen, disruption of the lobular structure, and impaired hepatocellular function frequently lead to systemic involvement and fatal complications. Drugs inhibiting collagen hydroxylation and accumulation are expected to improve this situation, making prolyl 4-hydroxylase (P4H), the key enzyme of intracellular collagen processing, a rational target for pharmacological intervention. S 4682, a novel inhibitor of purfied P4H (K_i = 155 nmol/L), reduced hydroxyproline (Hyp) synthesis in chicken embryo calvaria (IC₅₀ = 8.2 μmol/L) and in cultured hepatic stellate cells (HSC) (IC₅₀ = 39 μmol/L). S 4682 inhibited hepatic collagen hydroxylation in vivo after metabolic labeling with [¹⁴C]proline. In the CCl₄ model of chronic hepatic injury, characterized by histologically and biochemically evident fibrosis and highly elevated levels of serum procollagen type III N-peptide, S 4682 reduced hepatic collagen accumulation, decreased prevalence of ascites, and lowered serum procollagen type III N-peptide (PIIINP) levels. The hepatic Hyp content of drug-treated animals was closely correlated with serum levels of PIIINP. S 4682 had no influence on Hyp content of heart, lung, and kidney.