Target cells for the polychlorinated biphenyl metabolite 4,4'-bis(methylsulfonyl)-2,2',5,5'-tetrachlorobiphenyl. Characterization of high affinity binding in rat and mouse lung cytosol

J. Lund, I. Brandt, L. Poellinger, A. Bergman, E. Klasson-Wehler, Jan-Ake Gustafsson

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Abstract

When a tritium-labeled metabolite of polychlorinated biphenyls (PCB), 4,4'-bis([3H]methylsulfonyl)-2,2',5,5'-tetrachlorobiphenyl [(3H-MeSO2)2TCB] is administered intraperitoneally to rats, a selective labeling is registered in the apical cytoplasm of the nonciliated bronchiolar (Clara) cells of the lung as determined by microautoradiography of sections of methacrylate-embedded tissue. In vitro, (3H-MeSO2)2TCB binds with high affinity (Kd = 2.5-15 nM) and high capacity (B(max) = 30-70 pmol/mg of protein) to rat lung cytosol. Binding of (3H-MeSO2)2TCB to the high affinity sites is temperature dependent, reversible, and saturable. The sites seem to reside within a protein-like component, since proteolytic enzymes significantly reduce the binding. Physicochemical characterization of the (3H-MeSO2)2TCB-binding protein indicates a Stokes radius of 22 Å and a sedimentation coefficient of 1.7 S and, on the basis of these parameters, an apparent molecular weight of 16,000 may be calculated. The binding entity has an apparent pI of 5.3 and elutes as a single radioactive peak from CM-Sepharose at 75 mM acetate. Binding with similar affinities (IC50 values, 4-65 nM) is shown to occur also with other PCB methyl sulfones, whereas only one PCB, 2,2',4,4'5,5'-hexachlorobiphenyl, competes for (3H-MeSO2)2TCB binding, but with a lower affinity (IC50 = 3 μM). Among other compounds tested, only progesterone and some derivatives thereof display an affinity for the (3H-MeSO2)2TCB-binding protein (IC50 values ranging from 1 to 10 μM). Lung cytosol shows by far the highest amount of specific (3H-MeSO2)2TCB binding. However, low but detectable amounts are also found in cytosolic preparations from prostate, kidney, and large intestine. Finally, (3H-MeSO2)2TCB also binds to an entity in mouse lung cytosol with the same physicochemical characteristics as that in rat lung cytosol and to a progesterone-binding protein purified from rabbit uterus (uteroglobin). It is concluded that rat lung contains a uteroglobin-like macromolecule with a pronounced affinity for at least certain PCB methyl sulfones, and it is suggested that this binding entity is responsible for the striking accumulation of such metabolites in lung tissue following administration of PCB to rats and mice.

Original languageEnglish (US)
Pages (from-to)314-323
Number of pages10
JournalMolecular Pharmacology
Volume27
Issue number2
StatePublished - May 23 1985

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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