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Coordinate induction of cytochrome P-448 mediated mixed function oxidases and histopathologic changes produced
Abstract:
Hepatic histologic changes and induction of mixed function oxidases were examined and compared after administration to the chick embryo of four highly purified polychlorinated biphenyl (PCB) congeners: 3,4,3',4'-tetrachlorobiphenyl (TCB) and 3,4,5,3',4',5'-, 2,4,5,2',4',5'-, and 2,3,6,2',3',6'-hexachlorobiphenyls (HCBs). The major histopathologic change was hepatocyte swelling as evidenced by sinusoidal narrowing. It was observed within 24 hr after PCB administration at doses as low as 5 nmol/egg for 3,4,3',4'-TCB and 3,4,5,3',4',5'-HCB and only at doses of 5000 nmol/egg and higher for 2,4,5,2',4',5'-HCB. 2,3,6,2',3',6'-HCB was inactive. The histopathologic change was predominantly perivascular in distribution. It was accompanied by increased hepatic water content. Occasional hepatocytes showed nuclear pyknosis and cytoplasmic eosinophilia, but there was little histologic evidence of frank necrosis and no biochemical evidence, since serum glutamic-oxalic and glutamic-pyruvic transaminases and lactic dehydrogenase did not increase. Hepatic glutathione (GSH) levels were not significantly altered by 3,4,3',4'-TCB or 3,4,5,3',4',5'-HCB, indicating that GSH depletion does not have a significant role in the production of hepatotoxic changes by PCBs. Measurement of the degree of pathologic change indicated that 3,4,3',4'-TCB and 3,4,5,3',4',5'-HCB were three to four orders of magnitude more potent than 2,4,5,2',4',5'-HCB both as hepatotoxins and as inducers of the cytochrome P-448 mediated mixed function oxidases, aryl hydrocarbon hydroxylase, and 7-ethoxyresorufin deethylase. 2,3,6,2',3',6'-HCB was inactive as an inducer as well as as a hepatotoxin. The findings indicate that hepatotoxic changes are selectively produced in the chick embryo by those PCBs that also induce cytochrome P-448 mediated mixed function oxidases and in that respect resemble other manifestations of PCB toxicity (e.g., subcutaneous and pericardial edema and thymic involution) in both the chicken and other species. The results support the hypothesis that a common initial mechanism leads both to cytochrome P-448 type induction and to diverse manifestations of polyhalogenated hydrocarbon toxicity.