hydroxylysine and Abnormalities--Drug-Induced

Hydralazine (1-hydrazinophthalazine) produces skeletal defects resembling those observed in experimentally induced manganese deficiencies. Since glycosylation of collagen, a step preceding its secretion, requires Mn2+, the effect of hydralazine on collagen secretion and the formation hydroxylysine glycosides was examined in explants of embryonic chicken long-bone rudiments. Auto-radiographic studies showed that hydralazine blocked collagen secretion. Secretion was restored by Fe2+ alone or Fe2+ + Mn2+ but not by Mn2+ alone, suggesting that a Fe2+-requiring step was involved. Biochemical analyses showed that hydralazine inhibited the formation of hydroxylysine, a step requiring Fe2+, but it did not inhibit the formation of hydroxylysine-glocosides by Mn2+-requiring steps, although the reaction was inhibited in vitro. Hydralazine also failed to inhibit intracellular mucopolysaccharide synthesis which involves several Mn2+-requiring enzymes. These observations suggest that the deleterious effects of hydralazine on bones are caused by its inhibition of hydroxylation steps in collagen synthesis.

Topics: Abnormalities, Drug-Induced; Animals; Bone and Bones; Cartilage; Chick Embryo; Collagen; Depression, Chemical; Ferrous Compounds; Glycosides; Hydralazine; Hydroxylation; Hydroxylysine; In Vitro Techniques; Lysine; Manganese; Proline