Irreversible binding with biological macromolecules and effects in bacterial mutagenicity tests of the radical cation of promethazine and photoactivated promethazine. Comparison with chlorpromazine.
The irreversible binding of the radical cation of promethazine (PMZ+.) to DNA and protein in vitro and bacterial macromolecules in situ has been studied. Binding experiments were performed with synthesized [35S] promethazine. The results are compared to those with the chlorpromazine radical cation (CPZ+.). Secondary reaction products which result from fission of the alkylamino side chain are involved in the macromolecular binding of PMZ+. Compared to CPZ+. the covalent DNA binding of PMZ+. is significantly less. A larger amount of PMZ+. binds to single-stranded DNA than to double-stranded DNA. The extent of binding to proteins and RNA is of the same order as that of CPZ+. Bacterial mutagenicity tests show that the low genotoxicity of PMZ+. is related to the low DNA binding. The bacterial cytotoxicity is possibly related to the covalent protein binding. Similar results have been obtained with photoactivated promethazine (PMZ) and chlorpromazine (CPZ). The role of radical cations in the photosensitization and metabolic activation of phenothiazine drugs is discussed.
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De Mol
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Becht
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Koenen
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Lodder
D000818:Animals; D001665:Binding Sites; D001711:Biotransformation / Q000528:radiation effects; D002412:Cations; D002417:Cattle; D002746:Chlorpromazine / Q000378:metabolism / Q000528:radiation effects / Q000633:toxicity*; D004247:DNA / Q000378:metabolism; D004260:DNA Repair / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics; D009152:Mutagenicity Tests; D009153:Mutagens; D010777:Photochemistry; D011398:Promethazine / Q000378:metabolism / Q000528:radiation effects / Q000633:toxicity*; D011485:Protein Binding; D012313:RNA / Q000378:metabolism; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics
D002412:Cations; D009153:Mutagens; D012313:RNA; D004247:DNA; D011398:Promethazine; D002746:Chlorpromazine