alpha-Fluoromethylhistidine. Kinetics of uptake and inhibition of histamine synthesis in basophil (2H3) cell cultures.

Labeled histidine was taken up into rat leukemic basophil 2H3 cells by a system with high affinity for histidine and then decarboxylated to form histamine. Uptake was partially inhibited and decarboxylation was completely blocked by alpha-fluoromethylhistidine (alpha-FMH) at concentrations of 10-100 microM. alpha-FMH appeared to be co-transported by a histidine uptake system but the affinity of the system for alpha-FMH was lower than that for histidine (Km 130 and 24 microM, respectively). The drug rapidly penetrated into and became highly localized within the cells. By 60 min the apparent IC50 for inhibition of histamine synthesis in intact cell suspensions was 0.2 microM compared to an IC50 of 1-2 microM alpha-FMH for inhibition of soluble histidine decarboxylase preparations. Turnover of histidine decarboxylase activity in 2H3 cells was rapid (t1/2, 37 min), and biphasic effects were noted after 24-h exposure of 2H3 cells to drug. At low concentrations (greater than 0.1 microM), decarboxylase activity was increased (up to 134 +/- 9% of control values). Higher concentrations of the drug (0.1-10 microM) were inhibitory, and inhibition was related to drug concentration. No detectable decarboxylase activity was observed with 10 microM alpha-FMH after 4 days. Histamine levels increased (up to 232 +/- 2% of control values) or decreased in parallel with decarboxylase activity. Even in cultures devoid of histamine or decarboxylase activity (with 10 microM alpha-FMH) cell division and growth were not affected. Thus the drug appeared to inhibit specifically histamine synthesis without impairing essential cellular metabolic processes. However, kinetics of drug uptake and perturbation of enzyme turnover are additional factors to be considered in the action of alpha-FMH in intact cell systems.