D-Penicillamine and BAPN (β-amino propionitrile) were found to be the most active agents able to cause an accumulation of neutral salt-soluble collagen in the skin of rats. Most analogues of penicillamine had very little or no effects. Blocking the α-amino group (N-acetyl-penicillamine) or removal of the sulfhydryl group (valine) render inactive compounds. A higher homologue (mercaptoisoleucine) was ineffective. It would seem that the structure of D-penicillamine meets all the criteria for effectiveness, such as extracellular distribution, lack of metabolic deamination, sufficient amount of steric hindrance of the sulfhydryl group to retard its oxidation to disulfide, but yet not enough to prevent completely its reactivity. D-Penicillamine totally blocks the crosslinking of newly formed tropocollagen and is able to degrade a certain fraction of the more recently sythesized process insoluble collagen which has not yet completed its maturation D-Penicillamine affects equally both sexes, is more effective in young rats than in older ones and is not antagonized by copper if this metal is administered by a different route. If given simultaneously, mixed in the diet, the effect on collagen is inhibited and the toxicity of copper reduced, probably due to the marked affinity of both compounds and possible inactivation in the gastrointestinal tract. The urinary excretion of hydroxyproline in the D-penicillamine-treated rats falls within normal limits. Only the BAPN-treated animals showed an increase in urinary hydroxyproline. Since BAPN causes severe osseous abnormalities, whereas penicillamine does not, these findings would tend to support the view that an increase in urinary hydroxyproline is primarily a manifestation of abnormal metabolism of bone collagen. © 1969.
