Properties of the 2,3,7,8-TCDD receptor- a QSAR approach
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The Ah or 2,3,7,8-TCDD receptor protein plays an important role in mediating the biologic, toxic and genotoxic effects of aryl and halogenated aryl hydrocarbons. An assessment of the physicochemical parameters which facilitate ligand: receptor interactions was determined by multiple parameter linear regression analysis of the relative receptor binding affinities of a series of 7-substituted-2,3-dichlorodibenzo-p-dixoins (Eq 1), 8-substituted-2,3-di (Eq. 2) and 2,3,4-trichlorodibenzofurans (Eq 3). The results demonstrate that substituent lipophilicity (π) and molecular volumes were Eq. 1log (I/EC 50 ) = 1.24 π + 6.10Eq. 2log (I/EC 50 ) = 1.10 π + 5.19Eq. 3log (I/EC 50 ) = 1.09 π + 5.77. the major determinant factors governing interactions between the rat hepatic cytosolic receptor protein and the diverse substituted ligands. It has been shown that there are marked differences in species sensitivity to 2,3,7,8-TCDD (i.e. guinea pig > rat ∼ maice > hamster) although hepatic receptor levels in these species are comparable. QSAR analysis of the receptor binding EC 50 data for the 7-substituted-2,3-dichlorodibenzo-p-dioxins using rat (Eq. 1), mouse (Eq. 4), guinea pig (Eq. 5) and hamster (Eq. 6) hepatic cytosol demonstrated that there were significant differences in these equations. However it was also noted that Eq. 4log (I/EC 50 ) = 0.95 + 0.93 E s + 5.28Eq. 5log (I/EC 50 ) = 0.94 + 0.579 σ p + 6.13Eq. 6log (I/EC 50 ) = 0.70 + 1.227 σ p + 6.38. physicochemical factors which are important for ligand-receptor interactions were identical for the most sensitive (guinea pig) and least sensitive (hamster) species. These results indicate that events which follow the initial ligand-receptor interaction must be the major factors which determine species sensitivity to 2,3,7,8-TCDD. © 1986.
author list (cited authors)
Safe, S., Fujita, T., Romkes, M., Piskorska-Pliszczynska, J., Homonko, K., & Denomme, M. A.