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Inhibition of Collagen Crosslinking: Amino Nitriles and D-Penicillamine

Lathyrism is a connective tissue disorder associated with the ingestion or injection of BAPN (β-amino propionitrile and its chemical analogues), extracts of the sweet pea, or other members of the lathyrus family usually consumed during periods of great famine. The skeletal changes observed differ among species and vary with age, being much more pronounced in younger animals. The epiphyseal plate is a prime target.

The connective tissue abnormalities are associated with crosslinking defects in collagen and elastin. They are revealed by an increased solubility in hypertonic neutral salt solutions, due to an inhibition of lysyl oxidase activity. Since Cu2+deficiency also inhibits the enzymatic activity, the similarities of the defects induced by these two mechanisms are readily explainable.

Administration of penicillamine to animals and humans also causes an accumulation of neutral salt soluble collagen in skin and various soft tissues. Two of the more characteristic properties of penicillamine, namely the ability to trap carbonyl compounds and to chelate heavy metals, are of primary significance in impairing collagen crosslinking. The former property manifests itself in all effective dose ranges, whereas the latter occurs only at dosages far higher than those administered to humans.

The collagen extracted from tissues of animals treated with D-penicillamine is able to form stable fibers in vitro and is not deficient in aldehydes, as is that from BAP-treated animals. In fact, its aldehyde content is even higher than normal, suggesting that the mechanisms of action of BAPN and penicillamine are different.

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