SELECTIVE-INHIBITION OF HEPATIC COLLAGEN ACCUMULATION IN EXPERIMENTALLIVER FIBROSIS IN RATS BY A NEW PROLYL 4-HYDROXYLASE INHIBITOR

Fibrosis and cirrhosis of the liver are often the result of chronic li ver damage by a variety of different agents. Pathological accumulation of collagen, disruption of the lobular structure, and impaired hepato cellular function frequently lead to systemic involvement and fatal co mplications, Drugs inhibiting collagen hydroxylation and accumulation are expected to improve this situation, making prolyl 4-hydroxylase (P 4H), the key enzyme of intracellular collagen processing, a rational t arget for pharmacological intervention. S 4682, a novel inhibitor of p urified P4H (K-i = 155 nmol/L), reduced hydroxyproline (Hyp) synthesis in chicken embryo calvaria (IC50 = 8.2 mu mol/L) and in cultured hepa tic stellate cells (HSC) (IC50 = 39 mu mol/L). S 4682 inhibited hepati c collagen hydroxylation in vivo after metabolic labeling with [C-14]p roline. 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 s erum procollagen type III N-peptide (PIIINP) levels. The hepatic Hyp c ontent of drug-treated animals was closely correlated with serum level s of PIIINP. S 4682 had no influence on Hyp content of heart, lung, an d kidney.