The inhibition of lysyl oxidase in vivo by isoniazid and its reversal by pyridoxal. Effect on collagen cross-linking in the chick embryo.
Isonicotinic acid hydrazide (isoniazid) causes a large increase in the salt-solubility of collagen when injected into chick embryos; this change is accompanied by the inactivation of lysyl oxidase (EC 1.4.3.13), the enzyme responsible for initiating cross-link formation in collagen and elastin. In addition, isoniazid markedly decreases the liver content of pyridoxal phosphate. The depletion of pyridoxal phosphate takes approx. 6 h, whereas the inhibition of lysyl oxidase and the increase in collagen solubility occur more slowly. A reversal of these effects of isoniazid can be produced by the subsequent injection of a stoichiometric amount of pyridoxal, supporting the role of pyridoxal as a cofactor for lysyl oxidase. Treatment of chick embryos with beta-aminopropionitrile, an irreversible inhibitor of lysyl oxidase, causes an inhibition of the enzyme, which begins to recover within 24 h but which is not affected by the administration of pyridoxal; with isoniazid inhibition, however, lysyl oxidase activity does not show any sign of recovery by 48 h. It is proposed that isoniazid may cause the inhibition of lysyl oxidase by competing for its obligatory cofactor, pyridoxal phosphate. The potential clinical implications in the therapeutic control of fibrosis are briefly discussed.
D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors*; D000818:Animals; D001842:Bone and Bones / Q000187:drug effects / Q000201:enzymology; D002356:Cartilage / Q000187:drug effects / Q000201:enzymology; D002642:Chick Embryo; D003094:Collagen / Q000378:metabolism*; D003513:Cycloheximide / Q000494:pharmacology; D006909:Hydroxyproline / Q000378:metabolism; D007538:Isoniazid / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008249:Protein-Lysine 6-Oxidase / Q000037:antagonists & inhibitors*; D011730:Pyridoxal / Q000494:pharmacology*; D011732:Pyridoxal Phosphate / Q000378:metabolism
D011730:Pyridoxal; D011732:Pyridoxal Phosphate; D003094:Collagen; D003513:Cycloheximide; D000594:Amino Acid Oxidoreductases; D008249:Protein-Lysine 6-Oxidase; D006909:Hydroxyproline; D007538:Isoniazid