Cytotoxicity and mutagenicity of polycyclic aromatic hydrocarbon ortho-quinones produced by dihydrodiol dehydrogenase.
Eight polycyclic aromatic hydrocarbon (PAH) ortho-quinones that can be generated by dihydrodiol dehydrogenase (DD) were examined for their cytotoxicity in H-4-II-e (rat hepatoma) cells and for their mutagenicity in the Ames test. Seven of the PAH otrtho-quinones were potent cytotoxins yielding IC50 values for cell survival in the range 1-30 microns. PAH ortho-quinones were grouped into three classes based on their cytotoxicity profiles: group I contained ortho-quinones (e.g., naphthalene-1,2-dione and 7,12-dimethylbenz[alpha]anthracene-3,4-dione) which reduced cell viability and cell survival; group II contained ortho-quinones (e.g., benz[alpha]anthracene-3,4-dione and 5-methylchrysene-1,2-dione which reduced cell survival but had no effect on cell viability; and group III contained ortho-quinones (e.g., benzo[alpha]pyrene-7,8-dione) which had a pronounced effect on cell viability but minimal effects on cell survival. Using hepatoma cell suspensions and rat liver subcellular fractions, it was found that ortho-quinones underwent preferential enzymatic one-electron redox-cycling and produced superoxide anion radical (O2-.) and/or ortho-semiquinone anion or alternant radicals. ortho-Quinones that reduced cell viability produced O2-. and caused the most total free radical formation, while those that reduced cell survival produced ortho-semiquinone anion or alternant radicals only. PAH ortho-quinones were also tested as direct-acting mutagens in Salmonella typhimurium tester strains TA97a, TA98, TA100, TA102 and TA104. They were found to be more mutagenic than the test mutagens used for each tester strain, and were predominantly frameshift mutagens. The presence of an activating system (Aroclor-induced rat liver S9 plus NADPH) did not increase the mutagenicity of ortho-quinones in tester strains that are sensitive to oxidative mutagens (TA102 and TA104). These data suggest that PAH ortho-quinones produced by DD are cytotoxic and mutagenic by different mechanisms. The mechanism of cytotoxicity involves the formation of reactive oxygen species and/or ortho-semiquinone anion or alternant radicals. The mechanism of mutagenicity is independent of free radical formation and is related to the ability of PAH orthooffinones to intercalate and covalently modify DNA.
Flowers-Geary
L
L
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia 19104-6084, USA.
Bleczinki
W
W
Harvey
R G
RG
Penning
T M
TM
D000818:Animals; D001564:Benzo(a)pyrene / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000378:metabolism; D002458:Cell Fractionation; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D005609:Free Radicals / Q000378:metabolism / Q000494:pharmacology; D015394:Molecular Structure; D009152:Mutagenicity Tests; D010088:Oxidoreductases / Q000378:metabolism*; D011084:Polycyclic Aromatic Hydrocarbons / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D011809:Quinones / Q000145:classification / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D012486:Salmonella typhimurium / Q000235:genetics; D013329:Structure-Activity Relationship; D014812:Vitamin K / Q000031:analogs & derivatives / Q000378:metabolism
D005609:Free Radicals; D011084:Polycyclic Aromatic Hydrocarbons; D011809:Quinones; D014812:Vitamin K; D001564:Benzo(a)pyrene; D010088:Oxidoreductases; C048338:trans-1,2-dihydrobenzene-1,2-diol dehydrogenase