PCBs: structure-function relationships and mechanism of action

Journal Article · Wed May 01 04:00:00 EDT 1985 · Environ. Health Perspect.; (United States)

DOI:https://doi.org/10.2307/3429944· OSTI ID:6080212

Safe, S; Bandiera, S; Sawyer, T; Robertson, L; Safe, L; Parkinson, A; Thomas, P E; Ryan, D E; Reik, L M; Levin, W; Denomme, M A

Quantitative structure-activity relationships within a series of PCBs were determined by comparing their aryl hydrocarbon hydroxylase (AHH) induction potencies (EC50) in rat hepatoma H-4-II-E cells and their binding affinities (ED50) for the 2,3,7,8-TCDD cytosolic receptor protein. The results showed that there was an excellent correlation between AHH induction potencies and receptor binding acidities of these compounds and the order of activity was coplanar PCBs (3,3',4,4'-tetra-, 3,3',4,4',5-penta- and 3,3',4,4',5,5'-hexachlorobiphenyls) > 3,4,4',5-tetrachlorobiphenyl approx. mono-ortho coplanar PCBs > di-ortho coplanar PCBs. It was also apparent that the relative toxicities of this group of PCBs paralleled their biological potencies. The coplanar and mono-ortho coplanar PCBs also exhibit differential effects in the inbred C57BL/6J and DBA/2J mice. These compounds induce AHH and cause thymic atrophy in the former responsive mice whereas at comparable or higher doses none of these effects are observed in the nonresponsive DBD/2J mice. Although the precise structural requirements for ligand binding to the receptor have not been delineated, the halogenated aromatic hydrocarbons which exhibit the highest binding affinities for the receptor protein are approximate isostereomers of 2,3,7,8-TCDD. 2,3,4,4',5-Pentachlorobiphenyl elicits effects which are qualitatively similar to that of TCDD and the presence of the lateral 4'-substituent is required for this activity. Thus the 4'-substituted 2,3,4,5-tetrachlorobiphenyls have been used as probes for determining the substituent characteristics which favor binding to the receptor protein.

• Research Organization: Texas A and M Univ., College Station
• OSTI ID: 6080212
• Journal Information: Environ. Health Perspect.; (United States), Journal Name: Environ. Health Perspect.; (United States) Vol. 60; ISSN EVHPA
• Country of Publication: United States
• Language: English

Related Subjects

560305* -- Chemicals Metabolism & Toxicology-- Vertebrates-- (-1987)
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ANIMALS
AROMATICS
BIOCHEMICAL REACTION KINETICS
CHLORINATED AROMATIC HYDROCARBONS
CYTOCHROME OXIDASE
DATA
DIOXIN
ENZYME ACTIVITY
ENZYMES
EXPERIMENTAL DATA
HAEM DEHYDROGENASES
HALOGENATED AROMATIC HYDROCARBONS
HETEROCYCLIC COMPOUNDS
HYDROXYLASES
INFORMATION
KINETICS
MAMMALS
MATHEMATICS
METABOLIC ACTIVATION
MICE
NUMERICAL DATA
ORGANIC CHLORINE COMPOUNDS
ORGANIC COMPOUNDS
ORGANIC HALOGEN COMPOUNDS
ORGANIC OXYGEN COMPOUNDS
OXIDOREDUCTASES
RATS
REACTION KINETICS
REGRESSION ANALYSIS
RODENTS
STATISTICS
STRUCTURE-ACTIVITY RELATIONSHIPS
TOXICITY
VERTEBRATES