Effects of individual terphenyls and polychlorinated terphenyls on rat hepatic microsomal cytochrome P-450-dependent monooxygenases: structure-activity relationships

B. D. Leece, M. A. Denomme, S. M.A. Li, R. A. Towner, J. W. Gyorkos, B. G. Chittim, S. Safe

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

The effects of o-, m- and p-terphenyl, 2,4-dichloro-, 2,4,6-trichloro-, 2,3,5,6-tetrachloro-, 2,3,4,6-tetrachloro-, 2,4,4'",6- tetrachloro- and 2,3,4,5-tetrachloro-p-terphenyl, 2,3,4,5-tetrachloro-m- and o-terphenyl as inducers of hepatic drug-metabolizing enzymes were determined in immature male Wistar rats. o-Terphenyl, 2,4-dichloro-, 2,4,6-trichloro-p-terphenyl and 2,3,4,5-tetrachloro-o-terphenyl induced 4,4′-dimethylamino antipyrine N-demethylase at total dose levels of 300 μmol/kg and the 2,3,4,5-tetrachloro-p-terphenyl induced ethoxyresorufin O-deethylase (EROD). In contrast, none of the other terphenyls or polychlorinated terphenyls (PCTs) induced these enzyme activities. Previous studies have demonstrated that 2,3,4,5-tetrachloro-p-terphenyl did not exhibit a high affinity for the 2,3,7,8-tetrachlorodibenzo-p-trachlorodibenzo-p-dioxin (TCDD) receptor protein (EC50= 6.6×10-6M). In contrast, this study showed that 2,3,4,5-tetrachloro-p-terphenyl was more active than either 2,3,4,5-tetrachloro-o- or m-terphenyl as an inducer of EROD. Moreover, the competitive receptor binding EC50 values for the latter two isomers were > 10-5 M and this result was also consistent with their lack of EROD induction activity. Previous studies showed that analysis of the data for a series of 4′-substituted-2,3,4,5-tetrachlorobiphenyls indicated that the p-terphenyl structural moiety (i.e. 4′-substituent = phenyl) did not interact with high affinity with the receptor protein binding site. Since the 2,3,4,5-tetrachloro o- and m-terphenyls are also poor ligands for the receptor protein, this data and results from other studies indicate that PCT congeners (and commercial mixtures) are therefore unlikely to elicit significant 2,3,7,8-TCDD-like biologic or toxic effects in target species.

Original languageEnglish (US)
Pages (from-to)186-189
Number of pages4
JournalArchives of Toxicology
Volume59
Issue number3
DOIs
StatePublished - Oct 1986

Keywords

  • Liver
  • Monooxygenases
  • Polychlorinated terphenyls
  • Rat
  • Receptor protein
  • SARS

ASJC Scopus subject areas

  • Toxicology
  • Health, Toxicology and Mutagenesis

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