Inhibition of the growth of the rat by L-penicillamine and its prevention by aminoethanol and related compounds.

Penicillamine (P,fl-dimethylcysteine) is a degradation product of all the known naturally occurring penicillins (1). It was first reported in 1943 (2). Since that time most investigations have dealt with its preparation, chemical properties, or relationship to penicillin, and little information is available regarding its biological behavior. The purpose of the present paper is to report the results of an investigat,ion of penicillamine as a possible metabolic antagonist. Some of these results have been reported in a preliminary note (3). Since penicillamine bears a structural resemblance to a number of naturally occurring amino acids, particularly cysteine, methionine, valine, and threonine, it occurred to us that penicillamine might act as a metabolic antagonist toward one of these amino acids. We found that addition of n-penicillamine to the diet did inhibit the growth of young rats on a 20 per cent casein diet and eventually led to death of the animals. However, cysteine, valine, and threonine failed to overcome this inhibition. The effect of methionine upon the response to penicillamine was equivocal and appeared to be affected by the presence of choline in the basal diet. When choline was removed from the diet, additional methionine did not counteract the effect of penicillamine. However, when choline was added to the diet in sufficient amounts without the additional methionine, the effects of penicillamine were completely overcome. To determine whether or not the quaternary ammonium structure was essential for this reversal of growth inhibition induced by penicillamine, dimethylaminoethanol and monomethylaminoethanol were investigated and were found to be as effective as choline. It then occurred to us that perhaps the methyl groups were not essential for the antipenicillamine activities of these compounds. Aminoethanol itself was tested and found to be even more effective than choline in overcoming the growth-inhibiting effects of L-penicillamine. The administration of n-penicillamine to rats was frequently followed by