COMPARATIVE ASPECTS OF TYROSINE HYDROXYLASE AND TRYPTOPHAN HYDROXYLASE INHIBITION - ARTERENONES AND DIHYDROXYPHENYLACETAMIDE (H22/54)

A bovine adrenal tyrosine hydroxylase preparation and a mouse mast cell tumor tryptophan hydroxylase have previously been shown to require a reduced pteridine cofactor. Both enzymes are inhibited in vitro by analogs of arterenone or β-keto-dihydroxyphenethylamines, and by H 22 54, a dihydroxyphenylacetamide, by an identical mechanism, i.e. competition with the reduced pteridine. Inhibition of tyrosine hydroxylase by H 22 54 was reduced by deleting exogenous Fe2+ from the incubate, but the inhibition by various arterenones and by α-methyltyrosine was not significantly altered. Both U-24, 274A, an arterenone analog, at 2000 mg/kg, and H 22 54 at 500 mg/kg reduced mouse brain norepinephrine. However, neither compound decreased mouse brain serotonin (5-HT); administration of either compound in combination with p-chlorophenylalanine (PCPA) also failed to diminish 5-HT levels below that produced by PCPA alone. Factors which may affect the specificity of enzyme inhibition in vivo are discussed. © 1968.