Involvement of different pathways in the genotoxicity of nitropropanes in cultured mammalian cells.
The metabolic pathways leading to genotoxicity of nitropropanes in mammalian cells were investigated by measuring the effects of 2-nitropropane (2-NP) and 1-nitropropane (1-NP) on various cell lines characterized for their expression of cytochrome P450-dependent mono-oxygenases. Cells used were the rat hepatoma cell lines 2sFou, H4IIEC3/G- and C2Rev7, which express various forms of cytochrome P450-dependent mono-oxygenases, and V79 Chinese hamster cells which lack these enzyme activities. Induction of DNA repair synthesis, micronuclei and, where assessable, mutations to 6-thioguanine (TG) resistance served as indicators of genotoxic effects. 2-NP elicited a positive response at all endpoints measured in the hepatoma lines after pretreatment of the cells with dexamethasone, an inducer of various liver-specific cytochrome P450 forms. Genotoxicity was much weaker or not detectable in cells not pretreated with the inducer. 1-NP was not genotoxic in the hepatoma cells irrespective of whether the cells were pretreated or not. Neither isomer elicited DNA repair synthesis in V79 cells, but both isomers caused mutations to TG resistance, and 1-NP increased the number of micronucleated and multinucleated cells. The findings show that there are different pathways in mammalian cells by which nitropropanes can be converted to genotoxic products. Presumably the induction of liver tumours by 2-NP is linked to the metabolic pathway which is characterized by the formation of genotoxic metabolites from 2-NP but not 1-NP. This pathway appears to depend on the presence of liver-specific, dexamethasone-inducible, cytochrome P450 forms. The relevance of the genotoxic effects of the nitropropanes observed in V79 cells for the situation in vivo is open to question.
Roscher
E
E
GSF-Institut für Toxikologie, Neuherberg/München, FRG.
Ziegler-Skylakakis
K
K
Andrae
U
U
D000473:Alkanes / Q000633:toxicity*; D000818:Animals; D001711:Biotransformation; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004260:DNA Repair / Q000187:drug effects; D004351:Drug Resistance; D008114:Liver Neoplasms, Experimental; D015162:Micronucleus Tests; D006899:Mixed Function Oxygenases / Q000096:biosynthesis; D009154:Mutation; D009595:Nitroparaffins / Q000378:metabolism / Q000633:toxicity*; D010105:Oxygenases / Q000378:metabolism; D011407:Propane / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D051381:Rats; D013866:Thioguanine / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000473:Alkanes; D009595:Nitroparaffins; C035314:1-nitropropane; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C019647:aldrin epoxidase; D010105:Oxygenases; D013866:Thioguanine; C016617:2-nitropropane; D011407:Propane