Inhibition of prolyl 4-hydroxylase in vitro and in vivo by members of a novel series of phenanthrolinones

Examples of a novel series of phenanthrolinones are shown to be potent comp etitive inhibitors of avian prolyl 4-hydroxylase, and of collagen hydroxyla tion, in embryonic chick tendon cells and human foreskin fibroblasts in vit ro and in the oestradiol-stimulated rat uterus in vivo. Two compounds, Comp ound 1 (1,4-dihydrophenanthrolin-4-one-3-carboxylic acid) and Compound 5 [8 -(N-butyl-N-ethylcarbamoyl)-1,4-dihydrophenathrolin-4-one-3-carboxylic acid ], with comparable potencies in ohio, were chosen to investigate the effect of the inhibition of the hydroxylation of newly synthesized uterine collag en on the turnover of this protein inf vivo. Inhibition of hydroxylation by more than 50 % for approx. 8 h following single oral doses of the compound s was associated with significant losses of radiolabelled proline and 4-hyd roxyproline from collagen during this period. Progressive hydroxylation of collagen over 48 h, as the inhibitory action of the compounds declined, was accompanied by a decreased loss of radiolabel from the uterine collagen. E arlier reports indicated that underhydroxylated collagen, accumulating with in the endoplasmic reticulum in cells where prolyl 4-hydroxylase is inactiv ated: is slowly degraded, but is then rapidly hydroxylated and secreted whe n the activity of prolyl 4-hydroxylase is restored. Taken with the present results, this suggests that the potential use of inhibitors of prolyl 4-hyd roxylase to control excessive collagen deposition in pathological fibrosis may be limited by the need to maintain continuous inhibition of collagen hy droxylation so as to facilitate intracellular degradation of the accumulate d protein.