Biochemical basis of skeletal defects induced by hydralazine: inhibiton of collagen synthesis and secretion in embryonic chicken cartilage in vitro.
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.
D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D000818:Animals; D001842:Bone and Bones / Q000002:abnormalities*; D002356:Cartilage / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism; D002642:Chick Embryo; D003094:Collagen / Q000096:biosynthesis / Q000378:metabolism*; D003864:Depression, Chemical; D005296:Ferrous Compounds / Q000494:pharmacology; D006027:Glycosides / Q000096:biosynthesis; D006830:Hydralazine / Q000009:adverse effects / Q000494:pharmacology*; D006900:Hydroxylation; D006901:Hydroxylysine / Q000096:biosynthesis; D066298:In Vitro Techniques; D008239:Lysine / Q000378:metabolism; D008345:Manganese / Q000494:pharmacology; D011392:Proline / Q000378:metabolism
D005296:Ferrous Compounds; D006027:Glycosides; D006830:Hydralazine; D006901:Hydroxylysine; D008345:Manganese; D003094:Collagen; D011392:Proline; D008239:Lysine