Factors influencing elevation of intracellular Ca2+ in the MCF-10A human mammary epithelial cell line by carcinogenic polycyclic aromatic hydrocarbons.
Carcinogenic polycyclic aromatic hydrocarbons and a halogenated aromatic hydrocarbon, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), were evaluated for their effects on intracellular Ca2+ in the human mammary epithelial cell line MCF-10A. After two 18-h incubations with MCF-10A cells, benzo[a]pyrene (BaP; 1, 3, and 10 microM) produced a dose-dependent increase in intracellular Ca2+. 7,12-Dimethylbenz[a]anthracene increased Ca2+ at 10 microM, whereas 3-methylcholanthrene and TCDD did not. The Ca2+-elevating effect of BaP appeared to be dependent on the influx of extracellular Ca2+, as addition of the Ca2+ chelator EGTA to the extracellular medium prevented the increase in Ca2+. MCF-10A cells were found by polymerase chain reaction to express cytochrome P4501A and P4501B isozymes as well as the aryl hydrocarbon receptor and aryl hydrocarbon receptor nuclear translocator mRNAs associated with cytochrome P450 induction. Certain cytochrome P450-derived metabolites, including benzo[a]pyrene-7,8-diol (BP-diol) and benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE), were more effective in increasing Ca2+ than was BaP. The Ca2+-elevating effect of BP-diol was prevented by alpha-naphthoflavone, a cytochrome P4501A and P4501B inhibitor, but not by the antioxidant N-acetylcysteine. These results suggest that cytochrome P450-dependent formation of BPDE from BP-diol is a major mechanism required for elevation of Ca2+ in MCF-10A cells.
Tannheimer
S L
SL
Toxicology Program, University of New Mexico College of Pharmacy, Albuquerque, USA.
Lauer
F T
FT
Lane
J
J
Burchiel
S W
SW
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000494:pharmacology; D015127:9,10-Dimethyl-1,2-benzanthracene / Q000494:pharmacology; D000111:Acetylcysteine / Q000494:pharmacology; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D001571:Benzoflavones / Q000494:pharmacology; D001580:Benzopyrenes / Q000494:pharmacology; D001940:Breast / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002273:Carcinogens / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins; D004101:Dihydroxydihydrobenzopyrenes / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004533:Egtazic Acid / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008748:Methylcholanthrene / Q000494:pharmacology; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D011084:Polycyclic Aromatic Hydrocarbons / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics
C497396:ARNT protein, human; D001571:Benzoflavones; D001580:Benzopyrenes; D002273:Carcinogens; D065607:Cytochrome P-450 Enzyme Inhibitors; D004268:DNA-Binding Proteins; D004101:Dihydroxydihydrobenzopyrenes; D000072317:Polychlorinated Dibenzodioxins; D011084:Polycyclic Aromatic Hydrocarbons; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D014157:Transcription Factors; C017228:benzo(a)pyrene 7,8-dihydrodiol; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D004533:Egtazic Acid; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D008748:Methylcholanthrene; D015127:9,10-Dimethyl-1,2-benzanthracene; C011512:alpha-naphthoflavone; D003577:Cytochrome P-450 Enzyme System; D002118:Calcium; D000111:Acetylcysteine