Structure-activity relationships in halogenated biphenyls: unifying hypothesis for structural specificity.
Using chlorinated biphenyls as model halogenated aromatic hydrocarbons, in this and previous work we have investigated the specific structural requirements for induction of cytochrome P-448, P-450 and associated monooxygenase activities, and exquisite toxicity in the guinea pig. The requirement of planarity of coplanarity was examined using single crystal X-ray techniques to describe the structure and conformation of PCBs and PBs in the solid state as an approximation of their interactions with a bioreceptor. It was concluded that the most stable conformation of all biphenyls with or without ortho-substitutents is non-planar and that neigher planarity nor symmetry is an inherent requirement for receptor binding. The basic requirement for toxic structures was the availability of at least three lateral bromines or four lateral chlorines arranged in about a 3 X 10 A triangle or box, respectively. The underlying factor in the apparent symmetry requirement (as determined by the number and positions of halogens) is net polarizability of the molecule. Sufficient polarization for binding requires four lateral chlorines or three lateral bromines. Planarity or coplanarity of rings is necessary only to effect juxtaposition of the four lateral chlorines, and binding is therefore facilitated by an increased population of planar conformers. The population of planar conformers in biphenyls is in turn reduced by the degree of ortho substitution and hindrance to rotation about the pivot bond. Net polarizability is increased by the buttressing effect of adjacent chlorines or bromines, especially when ortho positions are involved. Coplanarity effects steric fit to the receptor while polarizability effects binding affinity. Excessive buttressing may lower binding affinity. Some variation in these properties through molecular conformational preferences in the biphenyls is thought to explain the apparent 'mixed induction' seen for certain isomers. This is a unifying hypothesis for structural specificity based on the available and definitive crystallographic, theoretical and toxicological data on these pure compounds.
D001713:Biphenyl Compounds / Q000494:pharmacology*; D019388:Cytochrome P-450 CYP1A2; D003580:Cytochromes / Q000096:biosynthesis; D004790:Enzyme Induction / Q000187:drug effects; D006581:Hexachlorobenzene / Q000494:pharmacology; D008958:Models, Molecular; D008968:Molecular Conformation; D011075:Polybrominated Biphenyls / Q000494:pharmacology*; D011078:Polychlorinated Biphenyls / Q000494:pharmacology*; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D013329:Structure-Activity Relationship
D001713:Biphenyl Compounds; D003580:Cytochromes; D011075:Polybrominated Biphenyls; D000072317:Polychlorinated Dibenzodioxins; D006581:Hexachlorobenzene; D011078:Polychlorinated Biphenyls; C017170:Cyp1a2 protein, rat; D019388:Cytochrome P-450 CYP1A2