INHIBITION OF COLLAGEN HYDROXYLATION BY LITHOSPERMIC ACID MAGNESIUM SALT, A NOVEL COMPOUND ISOLATED FROM SALVIAE-MILTIORRHIZAE RADIX

We have screened several chinese medicinal herbs for the presence of a ntifibrotic agents. An aqueous extract of Salviae miltorrhizae Radix w as found to inhibit collagen secretion by human skin fibroblasts witho ut affecting DNA or noncollagen protein synthesis. We have subsequentl y purified the material exhibiting the inhibitory activity and identif ied it as magnesium lithospermate. From its chemical structure this co mpound was predicted to be an inhibitor of the post-translational modi fying enzymes prolyl and lysyl hydroxylases in collagen biosynthesis. Accordingly, it decreased the extent of prolyl and lysyl hydroxylation s in collagen by approx. 50%. Added to cell extracts it inhibited both prolyl and lysyl hydroxylase activities, but only lysyl hydroxylase a ctivity when added to intact cells. Oral administration of this compou nd to mice led to a significant reduction of prolyl hydroxylation in n ewly-synthesized skin collagen. This naturally-occurring compound thus offers a potential means for treating fibrotic diseases, such as syst emic scleroderma and keloid.