Polychlorinated biphenyls as phenobarbitone-type inducers of microsomal enzymes. Structure-activity relationships for a series of 2,4-dichloro-substituted congeners

Mary Anne Denomme, Stelvio Bandiera, Iain Lambert, Leslie Copp, Lorna Safe, Stephen Safe

Research output: Contribution to journalArticlepeer-review

57 Scopus citations

Abstract

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 ethoxyresorufln 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 ≥ 2,3,4,5,6-pentachloro > 2,3,4,6-tetrachloro > 2,3,5,6-tetrachloro > 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-hexa-chlorobiphenyl congener also elicited a dose-response induction of two PB-inducible enzymes, aldrin epoxidase and dimethylaminoantipyrine N-demethylase.

Original languageEnglish (US)
Pages (from-to)2955-2963
Number of pages9
JournalBiochemical pharmacology
Volume32
Issue number19
DOIs
StatePublished - Oct 1 1983

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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