Structural Requirements for Lathyrogenic Agents

Abstract

Collagen protein is generally regarded as having a small turnover in the adult; in certain situations however, such as the return to normal of the postpartum uterus of the rat (1) or the remodelling of a badly aligned healing fracture of long bone, collagen fibrils are resorbed, but the mechanisms involved remain elusive. Since one of the effects of lathyrogenic agents is thought to be a loosening of intermolecular collagen bonding (2, 3), lathyrism provides a potentially useful means with which to study the process of the disorgaz3ization of the collagen fibril. One such study on the metabolism of C14-nitrile-labelled aminoacetonitrile in the weanling rat (4) showed a wide distribution of the labelled carbon, the major part of which however remained unidentified. A later study of the metabolism of labelled fl-aminopropionitrile (BAPN) led to the identification of the major metabolic product, cyanoacetic acid, itself non-lathyrogenic, but the nature of the active molecule and its site of action remain unknown (5-7). Attempts to seek common chemical denominators among known lathyrogens (8, 9), have met with little success with the exception of one study (10) in which it was shown that the lathyrogenic capacity of an organic nitrile is influenced by the presence of a reactive amino group. Yet another approach has been the search for a common functional denominator, such as that of monamine oxidase inhibition (11-13) or chelate formation (14), but these hypotheses remain unproven.The major obstacle to these latter approaches has been the lack of clearly defined criteria of lathyrogenic activity, resulting in the inclusion of compounds of dubious activity; the criteria of activity in the rat, the usual assay animal, have been weight loss, skeletal deformity, neurological manifestations, and angiorrhexis. A rigid adherence to these criteria however, is misleading in such cases as the mature guinea pig where the administration of BAPN results not in skeletal deformity and angiorrhexis but solely in increased amounts of collagen extractable from the skin (15). Another assay system which relies on

Modifications of Arterial Phenotype in Response to Amine Oxidase Inhibition by Semicarbazide

“…SCZ is the reference compound for inhibiting SSAO activity, but it was shown long ago to be able to inhibit collagen cross-linking, an effect that was attributed to LOX inhibition. 13,14 Alternatively, it has been suggested that SSAO could influence arterial vascular tone, although contradictory results have been reported. 9,15,16 Vidrio et al 9 have proposed that SSAO-mediated hydrogen peroxide production could increase vascular tone and enhance hydralazine-induced vasodilation.…”

Evidence of osteolathyrism among patients suffering from neurolathyrism in Bangladesh

“…These seeds accumulate b-aminopropionitrile (BAPN) in the form of its g-glutamyl derivative and BAPN inhibits cross linking between polypeptide chains during the synthesis of both collagen and elastin. The failure to form such links causes skeletal deformation and blood vessel fragility in experimental animals [Levene, 1962;O'Dell et al, 1966]. The inhibition of cross linking is dose dependent [Lee et al, 1990] and also results in a decrease in the elastic modulus of the bone [Lees et al, 1987].…”

Studies on the Mode of Action of Lathyrogenic Compounds

“…TEXT-FIO. 8. Spectra] absorption curves of acetic acid solutions of collagen from guinea pigs treated with BAPN; before and after treatment of collagen with 2,4-dinitrophenylhydrazine; examined with visible light.…”