Molecular Pharmacology, Vol 8, 770-779, Copyright © 1972 by the American Society for Pharmacology and Experimental Therapeutics

Effect of p-Chlorophenylalanine on Hydroxylation of Tryptophan in Pineal and Brain of Rats

¹ Department of Psychiatry, Stanford University School of Medicine, Stanford, California 94305

Tryptophan hydroxylase activity was measured in vitro in the pineal gland, brain stem, and cerebral cortex of rats after treatment with p-chlorophenylalanine. Enzyme activity in the brain stem or cortex, assayed at 10 µM tryptophan, decreased to 5% of control 1-3 days after treatment with p-chlorophenylalanine. Enzyme activity in the pineal remained at 60-75% of that in control rats. When the tryptophan concentration was greater than 100 µM, tryptophan hydroxylase activity in the pineal did not differ between control and p-chlorophenylalanine-treated rats. Tryptophan hydroxylase in the pineal is thus relatively resistant to inhibition with p-chlorophenylalanine.

p-Chlorophenylalanine depleted serotonin levels in the pineal as well as in the brain. Neither the pineal nor the brain could convert tracer doses of radioactive tryptophan to serotonin, indicating that the biosynthetic capacity was impaired by treatment of the rats with p-chlorophenylalanine. However, after injection of a large dose of L-tryptophan, the pineals of p-chlorophenylalanine-treated rats synthesized serotonin from tryptophan at almost the same rate as the pineals of control rats. Smaller doses of L-tryptophan were less effective in increasing serotonin levels. These results indicate that, although the pineals of p-chlorophenylalanine-treated rats retained tryptophan hydroxylase, the affinity of the enzyme for tryptophan was reduced.

The differential sensitivity to p-chlorophenylalanine of pineal tryptophan hydroxylase as compared to the enzyme from various brain regions suggests that the pineal enzyme has distinctive molecular properties.

Note:
ACKNOWLEDGMENTS The authors are very grateful to Dr. Arata Ichiyama, Department of Nutrition, Tokyo University Faculty of Medicine, for helpful suggestions. We would like to thank Mrs. Elizabeth Erdelyi and Mr. Humerto Garcia for their excellent technical assistance, and Mrs. Rosemary Schmele and Mrs. Judy Lookabill for their secretarial assistance.

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