Chlorinated biphenyl induction of aryl hydrocarbon hydroxylase activity: a study of the structure-activity relationship.

Of 16 halogenated biphenyls examined for their capacity to induce hepatic aryl hydrocarbon hydroxylase activity in the chicken embryo, only three congeners, 3,4,39,49-tetrachlorobiphenyl, 3,4,5,39,49,59-hexachlorobiphenyl, and 3,4,5,39,49,59-hexabromobiphenyl, were active. They were approximately equipotent in the chicken embryo, with ED50 values of approximately 90 nmoles/kg. These three chlorobiphenyl congeners also induced hepatic aryl hydrocarbon hydroxylase activity in C57BL/6J mice and rats, and they competitively bound the hepatic cytosol binding species thought to be the receptor for the induction of this enzyme. Among the halogenated biphenyls, there appear to be two structural requirements for induction of aryl hydrocarbon hydroxylase activity: the presence of at least 2 adjacent halogen atoms in the lateral positions of each benzene ring (positions 3,4,39,49 or 3,4,5,39,49,59) and the absence of halogen atoms adjacent to the biphenyl bridge (positions 2,6,29, and 69); such substitutions lead to marked nonplanarity of the molecule. The halobiphenyl congeners that induced aryl hydrocarbon hydroxylase activity did not induce aminopyrine N-demethylase activity (a measure of phenobarbital-like activity); however, some of the congeners that failed to induce aryl hydrocarbon hydroxylase activity did induce aminopyrine N-demethylase. This suggests that while the commercial mixture of chlorobiphenyls, Aroclor 1254, induces a mixed pattern of microsomal monooxygenase activity resembling the combined administration of 3-methylcholanthrene and phenobarbital, any given chlorobiphenyl congener appears to produce only a 3-methylcholanthrene-like or a phenobarbital-like response (or the congener may be devoid of both activities). 3,4,39,49-Tetrachlorobiphenyl, the prototype of the halobiphenyls that induce hepatic aryl hydrocarbon hydroxylase activity, is an approximate isostereomer of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,7,8-tetrachlorodibenzofuran, and 3,4,39,49-tetrachloroazoxybenzene, all of which induce hepatic aryl hydrocarbon hydroxylase activity but which are over 100-fold more potent. Conversion of 3,4,39,49-tetrachlorobiphenyl to a more rigid, planar analogue, 2,3,6,7-tetrachlorobiphenylene, produced a compound roughly equipotent to TCDD in inducing hepatic aryl hydrocarbon hydroxylase activity in the chicken embryo.