Biochemical basis of skeletal defects induced by hydralazine: Inhibition of collagen synthesis and secretion in embryonic chicken cartilage in vitro

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Abstract
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 of 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-glycosides 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.