The effect of NSD-1055 on tissue levels of histamine and spermidine in rat.

Abstract

The biochemical and pharmacological significance of histamine formed in the body is largely unknown. Furthermore, the physiological role of this potent monoamine is poorly understood. The origin of histamine in mammalian tissue is, like many of the other monoamines, the result of the intracellular decarboxylation of an amino acid, in this case histidine (1-3). The metabolic conversion of histidine to histamine is catalyzed by at least two distinct enzymes: (i) a specific L-histidine decarboxylase (EC 4.1.1.22) found only in some tissue and (ii) the ubiquitous nonspecific aromatic L-amino acid decarboxylase [also referred to as 3,4-dihydroxyphenylala-nine (DOPA) decarboxylase (EC 4.1.1.26)] (4, 5). Pyridoxal-5-phosphate is the essential enzyme cofactor for the activity of various L-amino acid decarboxylases (6), including histidine decarboxylase, in mammalian tissue (2, 7, 8). Bromo-3-hydroxybenzyloxyamine (NSD-1055) inhibits histidine decarboxylase (EC 4.1.1.22) in vitro (9) and blocks the formation of histamine in vivo; its administration leads to depletion of histamine from tissues and its decreased excretion in the urine of the rat (10). The development of an enzyme inhibitor affords a means of testing for the physiological role of histamine. It has been suggested that NSD-1055 inhibits enzyme activity by inactivating the essential cofactor pyridoxal-5-phosphate (9). On the other hand, kinetic studies (28) of inhibition by NSD-1055 and several other O-substituted hydroxylamines suggest that these agents are competitive inhibitors with respect to the substrate (histidine), the oxyamine group of NSD-1055 competing with the amino group of the substrate for a carbonyl site on the holoenzyme (28). There is non-mast cell histamine (11) in mammalian brain associated with isolated nerve endings (12-14). An inhibition of the histamine-forming enzymes and the resulting depletion of tissue histamine would be useful in testing for some of the functions that have been ascribed to histamine in the body.