The inhibition of lysyl oxidase in vivo by isoniazid and its reversal by pyridoxal. Effect on collagen cross-linking in the chick embryo

Abstract

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.

Treatment of cartilage with β-aminopropionitrile accelerates subsequent collagen maturation and modulates integrative repair

“…Since BAPN irreversibly inhibits lysyl oxidase [33], lysyl oxidase would seem likely to be produced by chondrocytes in order for crosslinking to occur following BAPN pre-treatment and washout. The time course of this recovery is approximately 24 hours in chick embryos [9], which agrees with the sharp decrease in extractable [3H]proline 1-2 days following BAPN treatment (Fig. 3(c)).…”

The inhibition of protein-lysine 6-oxidase by various lathyrogens. Evidence for two different mechanisms

“…The results (Fig. 1, Table 4) confirm our previous findings (Carrington et al, 1984) that INAHtreated embryos fail to recover anything like as well as BAPN-treated embryos by 24 h, but also show clearly that SCH-treated embryos behavejust like INAH-treated embryos in regard to recovery and totally unlike BAPN-treated embryos.…”

“…As a result of earlier work and these new SCH data, we are now clearer about the mechanisms of action of these three lathyrogens. Our first experiment confirms earlier experiments (Carrington et al, 1984) that INAH both increases collagen solubility in the chick embryo and lowers cartilage and bone lysine oxidase activity and liver pyridoxal phosphate content; treatment with pyridoxal reverse these three effects.…”

Spectroscopic studies of the reaction between bovine serum amine oxidase (copper-containing) and some hydrazides and hydrazines

“…Since no detailed studies exist on the reaction between copper-containing amine oxidases and hydrazides, we decided to investigate in more detail the reaction between BSAO and these hydrazides to obtain additional information on the binding site and its reactions. The study was extended to isoniazid, the hydrazide of isonicotinic acid widely used in the treatment of tuberculosis (Carrington et al, 1984), and to simple derivatives of benzoic acid and phenylacetic acid to test the effect on reactivity and spectroscopic properties of different hydrazides, respectively in view of possible pharmacological use and of an understanding of the protein molecular structure.…”