Cytotoxicity of polycyclic aromatic hydrocarbon o-quinones in rat and human hepatoma cells.
A novel pathway of polycyclic aromatic hydrocarbon (PAH) metabolism involves the oxidation of non-K-region trans-dihydrodiols by dihydrodiol dehydrogenase (DD) to yield PAH o-quinones whose cytotoxicity and genotoxicity are unknown. The cytotoxicity of several PAH o-quinones derived from this reaction [naphthalene-1,2-dione (NPQ), benzo[a]pyrene-7,8-dione (BPQ), and 7,12-dimethylbenz[a]anthracene-3,4-dione (DMBAQ)] was examined in rat (H-4IIe) and human (Hep-G2) hepatoma cells which are known to express DD. 2-Methylnaphthalene-1,4-dione (menadione), a known cytotoxic p-quinone, was used as a positive control. Hepatoma cells (1 x 10(6) cells/mL) were exposed to PAH o-quinones (1-100 microM) for 0-4 h, and cell viability and survival were measured and related to O2.- production and changes in redox potential [GSSG/GSH and NAD(P)+/NAD(P)H]. Three different modes of cytotoxicity were observed: (1) NPQ (no bay region) and DMBAQ (methylated bay region) were as cytotoxic as menadione in reducing cell survival but had less effect on cell viability. These o-quinones adversely affected GSH levels and the redox state of the cell and caused an increase in the production of O2.- in cell suspensions. This cytotoxicity was not enhanced by dicoumarol (10 microM), a DT-diaphorase inhibitor, implying that this enzyme is unable to prevent these PAH o-quinones from entering one-electron redox-cycles. (2) BPQ (bay region only) was the least cytotoxic of the PAH o-quinones studied. BPQ decreased cell viability (< 40% at 20 microM) but did not adversely affect cell survival or the redox state of the cell.(ABSTRACT TRUNCATED AT 250 WORDS)
Flowers-Geary
L
L
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia 19104-6084.
Harvey
R G
RG
Penning
T M
TM
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D001728:Dicumarol / Q000494:pharmacology; D005609:Free Radicals / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D009281:Naphthalenes / Q000378:metabolism / Q000633:toxicity; D010084:Oxidation-Reduction / Q000187:drug effects; D011083:Polycyclic Compounds / Q000378:metabolism / Q000633:toxicity*; D011809:Quinones / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D013379:Substrate Specificity; D013481:Superoxides / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014812:Vitamin K / Q000633:toxicity
D005609:Free Radicals; D009281:Naphthalenes; D011083:Polycyclic Compounds; D011809:Quinones; D013481:Superoxides; D014812:Vitamin K; D001728:Dicumarol; D016660:NAD(P)H Dehydrogenase (Quinone)