title: Synergistic activity of polynuclear aromatic hydrocarbon mixtures as aryl hydrocarbon (Ah) receptor agonists.
abstract: The relative potencies of benzo[a]pyrene and a complex mixture of polynuclear aromatic hydrocarbons (PAHs) produced as by-products of manufactured gas plant (MGP) residues as inducers of hepatic microsomal ethoxyresorufin O-deethylase (EROD) activity were determined in the B6C3F1 mouse. The ED50 values for the induction response were 78 and 65 mg/kg for benzo[a]pyrene and the MGP-PAH mixture, respectively. Analysis of the MGP-PAH mixture indicated that benzo[a]pyrene and other compounds containing four or more rings and which are known to induce EROD activity were only present as trace components of this mixture. A comparison of the EROD induction potencies of benzo[a]pyrene and the MGP-PAH mixture showed that the mixture was approximately 706 times more potent than expected based on its benzo[a]pyrene content (0.17%). This induced P-450 activity could significantly increase the metabolism of the carcinogenic PAHs and thereby modulate the overall carcinogenicity of the mixture. The apparent synergistic activity of the MGP-PAH mixture was further investigated by comparing the activities of this mixture and benzo[a]pyrene for several other aryl hydrocarbon (Ah) receptor-mediated responses including (i) induction of hepatic CYP1A1 mRNA levels, (ii) transformation of the rat cytosolic Ah receptor to a complex which binds to a dioxin responsive element, (iii) induction of EROD activity and (iv) antiestrogenicity in MCF-7 human breast cancer cells, and (v) inhibition of the splenic plaque-forming cell (PFC) response to both T cell-dependent and independent antigens in B6C3F1 mice. For the EROD and CYP1A1 mRNA induction and cytosolic transformation activities and immunosuppressive effects, the MGP-PAH mixture was approximately 100-900 times more potent as an Ah receptor agonist than expected based on its benzo[a]pyrene content. The synergistic activity was lower (19-fold) for the antiestrogenic response in MCF-7 cells. The reason for the synergistic effects of the MGP-PAH mixture were not due to contamination of the mixture by 2,3,7,8-tetrachlorodibenzo-p-dioxin and related compounds and the results suggest that the enhanced potency of the mixture is due to unknown interactions between the individual PAHs present in the mixture.
authors.affiliation: Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station 77843-4466.
authors.forename: K
authors.initials: K
authors.lastname: Chaloupka
authors.forename: N
authors.initials: N
authors.lastname: Harper
authors.forename: V
authors.initials: V
authors.lastname: Krishnan
authors.forename: M
authors.initials: M
authors.lastname: Santostefano
authors.forename: L V
authors.initials: LV
authors.lastname: Rodriguez
authors.forename: S
authors.initials: S
authors.lastname: Safe
mesh_terms: D000818:Animals; D001483:Base Sequence; D002273:Carcinogens / Q000494:pharmacology*; D002402:Cathepsin D / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004357:Drug Synergism; D004790:Enzyme Induction; D004792:Enzyme Precursors / Q000378:metabolism; D005260:Female; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D010088:Oxidoreductases / Q000096:biosynthesis; D011083:Polycyclic Compounds / Q000494:pharmacology*; D051381:Rats; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects*; D013154:Spleen / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D002273:Carcinogens; D004792:Enzyme Precursors; D011083:Polycyclic Compounds; D018336:Receptors, Aryl Hydrocarbon; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D019363:Cytochrome P-450 CYP1A1; C058345:procathepsin D; D002402:Cathepsin D