Effects of substituted 2-nitroimidazoles and related compounds on unscheduled DNA synthesis in rat hepatocytes and in non-transformed (BL8) and transformed (JB1) rat liver epithelial derived cell lines.
1. Using unscheduled DNA synthesis as an index, the possible interaction of a number of substituted nitroimidazoles, e.g. misonidazole, with cellular DNA has been investigated. Transformed (JB1), non-transformed (BL8) rat liver epithelial derived cell lines and freshly prepared rat hepatocytes have been used. 2. Under anaerobic or aerobic conditions, relative to cells exposed to a nitroquinoline-N-oxide standard, misonidazole and related nitroimidazoles were very poor at stimulating unscheduled DNA synthesis in JB1 or BL8 cells or in hepatocytes, even at the highest concentrations tested (10 mM). Under anaerobic conditions, metabolic activation did occur as judged from the time-dependent depletion of cellular reduced glutathione in all three cell types. 3. It was concluded that in hypoxic cells an important mode of action of such nitroimidazoles as chemotherapeutic sensitisers may be by their interaction with cellular thiols rather from their interaction with DNA. 4. Functionalisation of the nitroimidazole ring with a side chain containing an aziridine function, e.g. RSU-1069 (1-(2-nitro-1-imidazolyl)-3-(1-aziridinyl)-2-propanol), results in the induction of unscheduled DNA synthesis in cells exposed under both aerobic and anaerobic conditions. On a molar basis, however, this induction was not so great as that caused by the simple monofunctional alkylating agent 1-aziridineethanol itself. Methyl-substitution of the aziridine ring in RSU-1069 reduced the extent of unscheduled DNA synthesis. 5. With all the compounds tested, unscheduled DNA synthesis was greater in JB1 cells than in BL8s or in hepatocytes.
Suzangar
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M
MRC Toxicology Unit, Carshalton, Surrey, U.K.
White
I N
IN
Jenkins
T C
TC
Connors
T A
TA
D000818:Animals; D001388:Aziridines / Q000494:pharmacology; D002461:Cell Line, Transformed; D004247:DNA / Q000096:biosynthesis; D004260:DNA Repair / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000032:analysis; D008099:Liver / Q000378:metabolism*; D008297:Male; D009593:Nitroimidazoles / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D013329:Structure-Activity Relationship
D001388:Aziridines; D009593:Nitroimidazoles; C033132:aziridine; D004247:DNA; D005978:Glutathione