UVA-induced genetic effects of thioridazine, mesoridazine and sulforidazine: an in vitro study.
This in vitro study focuses on the UVA-induced reactions with DNA of thioridazine (TRZ), and two of its major metabolites (TRZ-2-sulfoxide or mesoridazine, MRZ; and TRZ-2-sulfone or sulforidazine, SRZ). TRZ binds covalently to DNA upon UVA-irradiation. Under comparable irradiation conditions, MRZ binds to a lesser extent and almost no binding was observed with SRZ. Besides, photo-induced genetic effects were investigated by means of a differential DNA repair test in E. coli. The photo-induced genetic effects in E. coli decreased from TRZ, MRZ to SRZ, which corresponds with their capacity for UVA-induced binding to DNA. TRZ, MRZ and SRZ differed in their rate of photodecomposition rather than in the intrinsic reactivity towards DNA of the instable intermediates formed. Irreversible binding to DNA was also observed upon treatment with peroxidase, which is known to oxidize phenothiazines via the formation of reactive radical cation species. As both the colour of the intermediate and its reactivity towards DNA were comparable for peroxidase treatment and exposure to UVA, we assume that the radical cation is the reactive species in the latter case as well.
Department of Medicinal Chemistry, Leiden University, The Netherlands.
S A
SA
Schoonderwoerd
G M
GM
Beijersbergen van Henegouwen
I R
IR
Panday
D000928:Antidepressive Agents / Q000378:metabolism*; D004247:DNA / Q000378:metabolism / Q000528:radiation effects*; D004260:DNA Repair; D004926:Escherichia coli / Q000187:drug effects / Q000528:radiation effects*; D008653:Mesoridazine / Q000378:metabolism*; D010544:Peroxidases / Q000378:metabolism; D010640:Phenothiazines / Q000378:metabolism*; D013881:Thioridazine / Q000378:metabolism*; D014466:Ultraviolet Rays
D000928:Antidepressive Agents; D010640:Phenothiazines; D008653:Mesoridazine; D004247:DNA; C040634:sulforidazine; D010544:Peroxidases; D013881:Thioridazine