Molecular Pharmacology, Vol 1, 31-46, Copyright © 1965 by the American Society for Pharmacology and Experimental Therapeutics

Effects of Barbital on Amino Acid Metabolism in Escherichia coli

¹ Department of Pharmacology, Stanford University School of Medicine, Palo Alto, California

Barbital (0.02 M) inhibits growth of E. coli B in a glycerol medium. The inhibition is partially overcome by addition of amino acids.

L-Alanine oxidation by intact cells is inhibited by barbital, but washed cells previously grown in barbital have an enhanced ability to oxidize alanine. The same effects are seen with cell-free extracts. Barbital does not inhibit alanine uptake or pyruvate oxidation.

Conversion of L-alanine to pyruvate is apparently accomplished by alanine racemase and a D-alanine oxidase. Barbital inhibits the latter competitively, but has no direct effect on the racemase. Cells grown in barbital have increased racemase and D-alanine oxidase activity. Both enzymes are also induced by L-alanine.

This E. coli system is considered as a model for studying effects of prolonged drug administration, such as the development of tolerance, addiction, and the withdrawal syndrome. It is proposed that enzyme inhibition by a drug may be followed by derepression of synthesis of the same enzyme. The resulting increase in amount of the enzyme, despite its partial inhibition, could restore normal enzyme activity. Withdrawal symptoms could appear when the derepressed enzyme is suddenly released from drug inhibition.

Note:
ACKNOWLEDGMENT This investigation was supported by Public Health Service research grants No. CA02797, from the National Cancer Institute (to Avram Goldstein), and No. AM08431, from the National Institute of Arthritis and Metabolic Diseases (to D. B. Goldstein).