Halogenated biphenyls as AHH inducers: effects of different halogen substituents.
4'-Iodo-, 4'-bromo-, 4'-chloro- and 4'-fluoro-2,3,4,5-tetrachlorobiphenyl were administered to immature male Wistar rats and the effects of this homologous series of 4'-halo-2,3,4,5-tetrachlorobiphenyls on the microsomal drug-metabolizing enzymes were determined. All the halogenated biphenyls increased microsomal benzo[a]pyrene hydroxylase (or aryl hydrocarbon hydroxylase, AHH), ethoxyresorufin (ER) O-deethylase and dimethylaminoantipyrine (DMAP) N-demethylase. The effects of the 4'-halo-2,3,4,5-tetrachlorobiphenyls on the microsomal enzyme activities and on the relative peak intensities and spectral shifts of the reduced cytochrome P-450:CO and ethylisocyanide (EIC) binding difference spectra were similar to those observed after coadministration of phenobarbitone (PB) and 3-methylcholanthrene (MC). The relative activities of the halogenated biphenyls were determined using two in vitro assays; namely cytochrome P-448 associated induction in rat hepatoma H-4-II E cells in culture and competitive binding to the hepatic cytosolic Ah receptor protein from male Wistar rats. Dose-response experiments for the iodo, bromo, chloro and fluoro analogs gave EC50(M) values of 8.5 x 10(-9), 6.6 x 10(-8), 5.7 x 10(-7), and 3.3 x 10(-5), and 1.5 x 10(-6), 2.5 x 10(-6), 4.1 x 10(-6) and 2.5 x 10(-5) for the Er O-deethylase induction and receptor binding assays respectively. The relative potencies of the 4'-halo-2,3,4,5-tetrachlorobiphenyls followed the order I greater than Br greater than Cl greater than F for both assays and differences in the EC50 values for the iodo and fluoro analogs were greater than three orders of magnitude for ER O-deethylase induction in rat hepatoma cells in culture. One possible explanation for these effects may be associated with differences in the polarizability of the laterally substituted halogen groups. However, other differences in the physico-chemical properties of the halogen atoms may also be important.
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis*; D001713:Biphenyl Compounds / Q000378:metabolism / Q000494:pharmacology*; D004790:Enzyme Induction; D006846:Hydrocarbons, Halogenated / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D001713:Biphenyl Compounds; D006846:Hydrocarbons, Halogenated; D001189:Aryl Hydrocarbon Hydroxylases