Enhancement of microsomal drug oxidation and glucuronidation in rat liver by an environmental chemical, polychlorinated biphenyl

Abstract

A polychlorinated biphenyl (PCB) compound, Clophen A 50, enhanced both hepatic aryl hydrocarbon hydroxylase and p-nitroanisole O-demethylase activities (7.5-fold and 16-fold, respectively), after treating the rats for 6 days with consecutive daily injections of Clophen A 50 (15 mg/kg i.p.). The treatment increased 3-fold the content of the carbon monoxide binding hemoprotein in liver microsomes, causing a concomitant shift in its reduced carbon monoxide absorbance peak to 448 nm. NADPH cytochrome c reductase, another component reaction of the microsomal mixed-function oxidase, was enhanced 1.5-fold in 6 days. A slight enhancement in the overall hydroxylation reactions was already observable 24 h after a single injection of Clophen A 50. The UDPglucuronosyltransferase activity of native liver microsomes was enhanced 3-fold in 6 days by the Clophen A 50 treatment of rats. The enhancement was, however, more pronounced, if the microsomes were treated in vitro with membrane-perturbing agents to activate the latent UDPglucuronosyltransferase before measuring its activity. After treatment for 6 days, the enhancement was about 6-fold in digitonin-treated, 5-fold in phospholipase C-treated and about 10-fold in trypsin-digested microsomes. No enhancement could be detected 24 h after a single Clophen A 50 injection. Aryl hydrocarbon hydroxylase activity was also enhanced in lung (5-fold), and kidney (8-fold) microsomes, whereas the microsomes from the duodenal mucosa exhibited no enhancement by a Clophen A 50 treatment of rats for 3 days. The data obtained support the assumption that PCBs form a new type of inducer group in enhancing the microsomal drug biotransformation. Both the monooxygenase complex and UDPglucuronosyltransferase differ in their properties from those after enhancement with the known types of inducers, exemplified by phenobarbital and 3-methylcholanthrene, respectively.