POLYCHLORINATED BIPHENYLS (PCBs) AS INDUCERS OF THE HEPATIC MICROSOMAL DRUG-METABOLIZING ENZYMES - EFFECTS OF STRUCTURE ON ACTIVITY
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The effects of structure on the activity of polychlorinated biphenyls (PCBs) as inducers of hepatic drug-metabolizing enzymes was evaluated by comparing their modes of induction to the classical inducers, phenobarbitone (PB), 3-methylcholanthrene (MC) and PB plus MC (coadmin-istered). Due to the structurally different PCB congeners which induce PB-type activity, it was not possible to accurately define structure-activity rules. It was noted that PCBs which possess 2,4-dichloro-,2,3,4-trichloro-and 2,4,5-trichloro-substitution patterns on both phenyl rings were the most potent PC-type inducers. PCBs which induce MC-type (or aryl hydrocarbon hydroxylase, AHH) activity must be substituted at both para positions and at two or more meta positions (but not necessarily on the same phenyl ring). The compounds defined by these rules, namely, 3,3, 4,4-tetra-3,4,45-tetra-, 3,3,4,4,5-penta- and 3,3,4,4,5,5,-hexachlorobiphenyl induce AHH activity in the rat and in rat hepatoma 4-H-II-E cells in culture and also bind to the cytosolic Ah receptor protein. Substitution of the four MC-type inducers with one ortho-chloro group yields a series of mixed-type inducers which also induce AHH activity and competitively displace 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) from the Ah receptor protein. The di-ortho substituted analogs of 3,3,4,4,-tetra-, 3,4,4,5-tetra, 3,3,4,4,5-penta- and 3,3,4,4,5,5-hexachlorobiphenyl have also been tested in the rat and only five congeners, 2,3,4,4,5-penta-, 2,2,3,34,4-hexa-, 2,2,3,4,4,5,-hexa-, 2,3,4,4,5,6-hexa- and 2,2,3,3,4,4,5-heptachlorbiphenyl induced AHH activity at relatively high dose levels. The results are consistent with the proposed mechanism of enzyme induction by 2,3,7,8-TCDD and related halogenated aromatics. 1981 by Freund Publishing House Ltd.
