Influence of DT diaphorase on the mutagenicity of organic and inorganic compounds.
The metabolic activation or detoxification of mutagens and carcinogens of several chemical classes was investigated in the presence of various rat liver and lung subcellular fractions and of dicoumarol, a specific inhibitor of DT diaphorase activity. His- Salmonella typhimurium strains were used as targets of mutagenicity. Dicoumarol partially prevented the metabolic activation of some promutagens, such as the heterocyclic amines 2-amino-3,4-dimethylimidazo[4,5-f]quinoline and 3-amino-1-methyl-5H-pyrido[4,3-b]indole, and a cigarette smoke condensate. Moreover, detailed experiments, also using purified enzyme, confirmed the participation of DT diaphorase in the metabolic reduction of 4-nitroquinoline N-oxide 4NQO and of hexavalent chromium [Cr(VI)] compounds. The results obtained provide evidence for broad involvement of DT diaphorase in the metabolism of both organic and inorganic mutagens and carcinogens. Moreover, they suggest a dual role of this enzyme, providing not only a cellular detoxifying system but also, with a few substrates, an activating mechanism.
D000818:Animals; D001711:Biotransformation; D003600:Cytosol / Q000378:metabolism; D001728:Dicumarol / Q000494:pharmacology; D008658:Inactivation, Metabolic; D008099:Liver / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009152:Mutagenicity Tests; D009153:Mutagens / Q000494:pharmacology*; D011808:Quinone Reductases / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D012486:Salmonella typhimurium / Q000187:drug effects*
D009153:Mutagens; D001728:Dicumarol; D011808:Quinone Reductases