Polychlorinated biphenyls as phenobarbitone-type inducers of microsomal enzymes. Structure-activity relationships for a series of 2,4-dichloro-substituted congeners.
Several polychlorinated biphenyl (PCB) isomers and congeners resemble phenobarbitone (PB) in their mode of induction of the hepatic drug-metabolizing enzymes; however, unlike PCBs which induce aryl hydrocarbon hydroxylase, no apparent structure-activity correlations have been reported. This study examines the effects of structure on the activity of a series of 2,4-dichloro-substituted biphenyls as inducers of several microsomal enzyme activities including dimethylaminoantipyrine N-demethylase, benzo[a]pyrene hydroxylase, aldrin epoxidase, and ethoxyresorufin O-deethylase. The results clearly illustrate a marked effect of structure on activity: all of the 2,4-dichloro-substituted PCBs resembled PB in their mode of induction. However, the potency of the induction response was dependent on the substitution pattern of the second phenyl ring (i.e. 2,3,4,5-tetrachloro greater than or equal to 2,3,4,5,6-pentachloro greater than 2,3,4,6-tetrachloro greater than 2,3,5,6-tetrachloro greater than 2,4,6-trichloro); the structure of the lower chlorinated ring also determined induction potency since the 2,4-dichloro-substituted PCBs were generally more active than their 4-chloro-substituted analogs, whereas the 2-substituted PCB homologs were inactive. The structural factors which typify the most active PB-type inducer, 2,2',3,4,4',5-hexachlorobiphenyl, include the presence of two para-, at least two meta- and two ortho-chloro substituents. In addition to the structure-activity correlations noted for PCBs, the 2,2',3,4,4',5-hexachlorobiphenyl congener also elicited a dose-response induction of two PB-inducible enzymes, aldrin epoxidase and dimethylaminoantipyrine N-demethylase.
D000818:Animals; D001579:Benzopyrene Hydroxylase / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003573:Cytochrome b Group / Q000378:metabolism; D015786:Cytochromes b5; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology*; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D003573:Cytochrome b Group; D008748:Methylcholanthrene; D015786:Cytochromes b5; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; D006899:Mixed Function Oxygenases; D010088:Oxidoreductases; C019647:aldrin epoxidase; D001579:Benzopyrene Hydroxylase; D019363:Cytochrome P-450 CYP1A1; D010089:Oxidoreductases, N-Demethylating; C023680:dimethylaminoantipyrine N-demethylase; D010634:Phenobarbital