Abstract

The effect of a new amino acid analogue, 2-fluoro-L-histidine, on the stimulation of certain enzyme activities in the rat pineal gland, mouse mammary gland, a hepatoma cell line, and rat liver explants was investigated. This compound inhibited the isoproterenol stimulation of pineal N-acetyltransferase activity in vivo, and in organ culture it blocked the isoproterenol, norepinephrine, and N⁶,2'-O-dibutyryladenosine 3',5'-monophosphate stimulation of this enzyme. Inhibitory effects of 2-fluorohistidine on the steroid induction of tyrosine aminotransferase in liver explants and on benz[a]anthracene induction of aryl hydrocarbon hydroxylase in established hepatoma cell line cultures were also observed. 2-Fluorohistidine did not block the spontaneous increase in ornithine decarboxylase activity in explants of mouse mammary gland, but did partially block the spontaneous increase of this enzyme in cultured pineal glands. In cultured pineal glands, no evidence was found for direct competitive or noncompetitive inhibition of N-acetyltransferase by 2-fluorohistidine, for the existence of any inhibitory effect on N-acetyltransferase activity in 2-fluorohistidine-treated glands, or for rapid irreversible toxic effects of this analogue. Unlike cycloheximide, which blocks the stimulation of pineal N-acetyltransferase activity by blocking protein synthesis, 2-fluorohistidine did not substantially inhibit the incorporation of [³H]leucine into protein. However, the incorporation of [¹⁴C]histidine is reduced by 50-90% in pineal glands treated with 2-fluorohistidine. This, together with the observation that the inhibitory effect of the analogue on enzyme induction and on [¹⁴C]histidine incorporation was reversed by an equal concentration of histidine, suggests to us that 2-fluorohistidine may act by competing with histidine in a metabolic pathway, perhaps protein synthesis.