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Molecular Pharmacology, Vol 18, 100-104, Copyright © 1980 by the American Society for Pharmacology and Experimental Therapeutics

Inhibition of Histamine-Metabolizing Enzymes and Elevation of Histamine Levels in Tissues by Lipid-Soluble Anticancer Folate Antagonists

DAVID S. DUCH 1, MARK P. EDELSTEIN 1, and CHARLES A. NICHOL 1

1 Department of Medicinal Biochemistry, WeLlcome Research Laboratories, Research Triangle Park, North Carolina 27709

Potent inhibitors of dihydrofolate reductase can differ widely in the extent to which they inhibit histamine N-methyltransferase. This difference in activity provided a basis for selecting drugs as candidate anticancer agents which would have minimal interference with histamine metabolism. The drugs were studied in vitro for their effects on histamine N-methyltransferase and diamine oxidase (histaminase), and in vivo for their effects on histamine levels. Of the drugs studied, a trimethoxybenzylaminoquinazoline (TMQ, JB-11) and two diaminopyrimidines, 2,4-diamino-5-(1-adamantyl)-6-methylpyrimidine and metoprine, were found to be the most potent inhibitors of histamine N-methyltransferase in vitro, having Ki, values of 7, 50, and 100 nM, respectively. TMQ and methasquin were potent inhibitors of diamine oxidase, having Ki, values of 4.1 and 3.7 µM, respectively. In vivo, TMQ produced significant elevation of histamine levels in rat brain and kidney. A dimethoxybenzylpyridopyrimidine (BW 301U), a novel lipid-soluble antifolate being advanced for study as an antineoplastic agent, was as potent as methotrexate as an inhibitor of dihydrofolate reductase and had minimal effects on histamine levels in vivo. The evidence presented suggests that in the design of novel antifolates the effects of the drugs on histamine metabolism should be determined. The same approach is applicable to other classes of drugs.

Submitted on October 29, 1979
Accepted on January 25, 1980




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