Radical production from peroxide and peracid tumour promoters: EPR spin trapping studies.
EPR spin trapping using the spin traps 5,5-dimethyl-1-pyrroline N-oxide (DMPO) and 3,5-dibromo-4-nitrosobenzene sulphonic acid (DBNBS) has been employed to examine the generation of radicals from a number of organic peroxides and peracids which are known or suspected tumour promoters. All of the compounds when incubated with rat liver microsomal fractions in the presence of NADPH or NADH are metabolised to radical species which can be detected, and in most cases identified definitively, as the corresponding spin adducts; the assignment of particular signals to certain spin adducts has been confirmed by photolytic experiments. In the majority of cases, the predominant species are the arenecarbonyloxyl [RC(O)O.] and hydroxyl radical adducts. The mechanism of formation of the former species is shown to be enzymatic and cytochrome P-450 dependent and requires the presence of reducing equivalents. This type of radical is shown to undergo ready decarboxylation to give aryl radicals in agreement with previous chemical studies. The detection of these radical species, which are known to cause DNA strand breaks and be cytotoxic, with all the compounds tested, provides strong supportive evidence for the theory that it is the generation of radical species from these compounds which is the cause of their tumour-promoting activity.
Department of Chemistry, University of York, UK.
T L
TL
Greenley
M J
MJ
Davies
D000818:Animals; D001557:Benzenesulfonates / Q000737:chemistry; D002273:Carcinogens / Q000737:chemistry*; D003497:Cyclic N-Oxides / Q000737:chemistry; D004578:Electron Spin Resonance Spectroscopy; D005609:Free Radicals; D008297:Male; D008862:Microsomes, Liver / Q000737:chemistry; D009603:Nitroso Compounds / Q000737:chemistry; D010545:Peroxides / Q000737:chemistry*; D010782:Photolysis; D051381:Rats; D013113:Spin Labels
D001557:Benzenesulfonates; D002273:Carcinogens; D003497:Cyclic N-Oxides; D005609:Free Radicals; D009603:Nitroso Compounds; D010545:Peroxides; D013113:Spin Labels; C017245:5,5-dimethyl-1-pyrroline-1-oxide; C048757:3,5-dibromo-4-nitrosobenzenesulfonate