The Lathyrogenic Effect of Isonicotinic Acid Hydrazide (Inah) on the Chick Embryo and Its Reversal by Pyridoxal

Abstract

Evidence has been previously presented to show that lathyrogenic agents increase the solubility of collagen and the fragility of the connective tissues in the chick embryo (1). Assay systems for the detection of lathyrogenic agents have hitherto relied upon loss of weight and morphological changes in the rat as criteria of activity. In the chick embryo however, skeletal deformity can occur in the absence of changes in collagen solubility, and vice versa (1). Since the changes in the functional properties of collagen were considered to be more fundamental than changes in morphology, an assay system has been used based on collagen solubility and tissue tensile properties in the chick embryo (2).The main interest in lathyrism stems from its usefulness as a tool with which to study mechanisms by which collagen, once laid down, may be mobilized, but so far studies on the lathyrogenic nitriles, such as fl-aminopropionitrile (BAPN), have failed to elucidate such mechanisms. During an investigation into the nature of chemical groups possessing lathyrogenic activity using the chick embryo assay method, it was repeatedly noted that isonicotinic acid hydrazide ("isoniazid" or INAH) a compound effective against tuberculosis, possessed marked lathyrogenic activity. This report discusses its mode of action, comparing it with that of BAPN, the reversal of the INAH effect by pyridoxal, and the possible relevance of these findings to mechanisms of collagen mobilization. Materials and MethodsFertile eggs of the White Leghorn variety were injected v/a the chorio-allantoic membrane with isonicotinic acid hydrazide (INAH)I or ~-aminopropionitrile (BAPN) 2 in distilled water

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

“…Strong evidence exists that pyridoxal phosphate is also necessary as a cofactor of lysyl oxidase (Levene, 1961a). Reagents which react with carbonyl groups [e.g.…”

“…phenylhydrazine, hydroxylamine (Harris et al, 1974), isoniazid (Arem & Misiorowski, 1976)] all inactivate the enzyme. Experiments in vivo with chicks have shown that inhibition of lysyl oxidase by a pyridoxinedeficient diet (Murray et al, 1978) or by lathyrogens (Levene, 1961a) can be reversed by pyridoxal or pyridoxine. Other aldehydes were less effective in reversing the effects of lysyl oxidase inhibition (Levene, 1961a).…”

Acquired Cutis Laxa: Case Report and Review of Disorders of Elastolysis

“…In the chick embryo, isoniazid has been shown to alter the collagen content and produce a lathyrogenic effect that is reversible by pyridoxal (32). Finally, the association of cutis laxa with allergic reactions to penicillin and with multiple myeloma raises the question of an immune-mediated mechanism.…”

“…Alternatively, Goltz et al (11) suggested that altered copper metabolism may be the primary defect in cutis laxa and an abnormality in serum copper may lead to dysfunction of a serum eiastase itihibitor. In the chick embryo, isoniazid has been shown to alter the collagen content and produce a lathyrogenic effect that is reversible by pyridoxal (32). Finally, the association of cutis laxa with allergic reactions to penicillin and with multiple myeloma raises the question of an immune-mediated mechanism.…”

Possibilities for the Therapeutic Control of Fibrosis

“…The compound which resolved the problem was isonicotinic acid hydrazide (isoniazid, INAH) which proved to be a lathyrogen (Levene, 1961a). As a result, lathyrogenic compounds fell, on an equimolar basis, into four groups of diminishing potency:…”