Benzo[a]pyrene and other inducers of cytochrome P1-450 inhibit binding of epidermal growth factor to cell surface receptors.
The binding of 125I-labelled epidermal growth factor (EGF) was utilized to monitor possible cell surface effects of polycyclic aromatic hydrocarbon carcinogens. Exposure of confluent C3H 10T1/2 mouse fibroblasts to 1 muM benzo[a]pyrene led to a time-dependent decrease of EGF binding. By 24 h, EGF binding was only 5% that of control cultures. In contrast, benzo[a]pyrene-7,8-diol-9,10-oxide did not significantly alter EGF binding, indicating that the inhibition by benzo[a]pyrene was not simply due to DNA damage. A curvilinear Scatchard plot in the control cells was consistent with the presence of two classes of EGF receptors having differing affinities. Our results suggest that the major effect of benzo[a]pyrene was a reduction in receptor number rather than affinity, although other interpretations have not been excluded. Progesterone, 17 beta-estradiol, benzo[e]pyrene, cholesterol, phenobarbital, 1,1-bis-(p-chlorophenyl)-2,2,2-trichloroethane, hexachlorobenzene or pregnenolone-16 alpha-carbonitrile, did not inhibit EGF binding. On the other hand, several known inducers of P1-450 were very effective inhibitors of EGF binding. These included: dimethylbenz[a]anthracene, 3-methylcholanthrene, benzo[a]pyrene, benz[a]anthracene, beta-naphthoflavone and alpha-naphthoflavone. We postulate that the binding of certain polycyclic aromatic hydrocarbons to the Ah receptor may induce not only specific drug metabolizing enzymes but also inhibition of EGF binding, and possible other cell effects. Further studies are required to verify this hypothesis.
D000818:Animals; D001564:Benzo(a)pyrene; D001580:Benzopyrenes / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007700:Kinetics; D051379:Mice; D008809:Mice, Inbred C3H; D011083:Polycyclic Compounds / Q000494:pharmacology; D013997:Time Factors
D001580:Benzopyrenes; D011083:Polycyclic Compounds; D001564:Benzo(a)pyrene; D004815:Epidermal Growth Factor; D003577:Cytochrome P-450 Enzyme System