SYNERGISTIC ACTIVITY OF POLYNUCLEAR AROMATIC HYDROCARBON MIXTURES AS ARYL-HYDROCARBON (AH) RECEPTOR AGONISTS

The relative potencies of benzo[a]pyrene and a complex mixture of poly nuclear aromatic hydrocarbons (PAHs) produced as by-products of manufa ctured gas plant (MGP) residues as inducers of hepatic microsomal etho xyresorufin O-deethylase (EROD) activity were determined in the B6C3F1 mouse. The ED(50) 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 compou nds containing four or more rings and which are known to induce EROD a ctivity were only present as trace components of this mixture. A compa rison of the EROD induction potencies of benzo[a]pyrene and the MGP-PA H mixture showed that the mixture was approximately 706 times more pot ent than expected based on its benzo[a]pyrene content (0.17%). This in duced P-450 activity could significantly increase the metabolism of th e carcinogenic PAHs and thereby modulate the overall carcinogenicity o f the mixture. The apparent synergistic activity of the MGP-PAH mixtur e was further investigated by comparing the activities of this mixture and benzo[a]pyrene for several other aryl hydrocarbon (Ah) receptor-m ediated responses including (i) induction of hepatic CYP1A1 mRNA level s, (ii) transformation of the rat cytosolic Ah receptor to a complex w hich binds to a dioxin responsive element, (iii) induction of EROD act ivity and (iv) antiestrogenicity in MCF-7 human breast cancer cells, a nd (v) inhibition of the splenic plaque-forming cell (PFC) response to both T cell-dependent and independent antigens in B6C3F1 mice. For th e EROD and CYP1A1 mRNA induction and cytosolic transformation activiti es and immunosuppressive effects, the MGP-PAH mixture was approximatel y 100-900 times more potent as an Ah receptor agonist than expected ba sed on its benzo[a]pyrene content. The synergistic activity was lower (19-fold) for the antiestrogenic response in MCF-7 cells. The reason f or the synergistic effects of the MGP-PAH mixture were not due to cont amination of the mixture by 2,3,7,8-tetrachlorodibenzo-p-dioxin and re lated compounds and the results suggest that the enhanced potency of t he mixture is due to unknown interactions between the individual PAHs present in the mixture.