Inhibition of histidine decarboxylases

Abstract

Histidine decarboxylases of mammalian origin are of two main types. One of these acts not only on histidine but also on other aromatic amino acids, notably L-3,4-dihydroxyphenylalanine (DOPA) and L-5-hydroxytryptophan. A typical example of this non-specific enzyme, for which the term aromatic L-amino acid decarboxylase has been suggested¹, is the histidine decarboxylase of guinea pig kidney. The other type of histidine decarboxylase, which is a specific enzyme acting only on histidine, occurs in mast cells², in certain rapidly growing tissues^3,4 and is formed adaptively in the micro-circulation under suitable conditions⁵. Apart from their different substrate specificities the two types of histidine decarboxylase can also be distinguished by their pH optima, reaction to benzene, and particularly by their response to inhibitors^2,3,6,7,8,9. Many compounds are known to inhibit non-specific histidine decarboxylase¹⁰, and to these must be added the many inhibitors of DOPA decarboxylase. For example α-methyl-DOPA¹¹ is a potent inhibitor not only of DOPA decarboxylase but also of non-specific histidine decarboxylase^12,13. Relatively few compounds are known to inhibit the specific histidine decarboxylase^9,14. Encouraging results obtained with α-methyl-DOPA in the treatment of hypertension have led to the synthesis of numerous other DOPA-decarboxylase inhibitors as potential therapeutic agents. We have now tested several such compounds for their ability to inhibit the non-specific and the specific histidine decarboxylases.