RELATIVE POTENCIES OF INDUCTION OF HEPATIC DRUG-METABOLIZING ENZYME GENES BY INDIVIDUAL PCB CONGENERS

The induction of a variety of drug-metabolizing enzymes by polychlorin ated biphenyl (PCB) congeners that elicit a 2,3,7,8,-tetrachlorodibenz o-p-dioxin (TCDD)-type hepatic pleiotropic response, including 2,3,3', 4,4'-pentachlorobiphenyl (BZ 105), 2,3',4,4',5-pentachlorobiphenyl (BZ 118), 2,3,3',4,4',5-hexachlorobiphenyl (BZ 156), and 3,3',4,4',5,5'-h exachlorobiphenyl (BZ 169) was examined. Following dietary exposure to the individual congeners for 5 days, livers were removed and catalyti c assays for cytochrome P450 (CYP) isozymes 1A1 and 1A2 were performed . Additionally, total cellular RNA coding for hepatic drug-metabolizin g genes (CYP 1A1, CYP 1A2, microsomal epoxide hydrolase, glutathione S -transferase [GST] Ya/Yc, and the TCDD-inducible isozyme of aldehyde d ehydrogenase [ALDH] was quantified. 3-Methylcholanthrene (MC), TCDD, o r BZ 156 (32 ppm) caused nearly maximal induction of the CYP 1A protei ns but lower induction of the other genes. When the dose-response curv es for induction of various drug-metabolizing genes (CYP1A1 and 1A2, m icrosomal epoxide hydrolase, the GST Ya/Yc subfamily and ALDH) were ex amined, a spectrum of ED50s (half-maximal inductions) was observed. Wh ile CYP 1A2 exhibited an ED50 of 1.7 ppm, the induction of ALDH was sh ifted far to the right (ED50 > 11 ppm). Thus, different genes in a sin gle tissue may display different dose-response characteristics. The po tency (extent of induction of CYP 1A1 activity resulting from a given dietary dose) was BZ 169 much greater than BZ 156 > BZ 118 > BZ 105. I n contrast, the potencies of the four congeners for CYP 1A1 induction were nearly equivalent when related to hepatic PCB burden, apparently due to the preferential accumulation in the liver of BZs 169 and 156 f ollowing low-level administration in the diet. (C) 1995 Academic Press , Inc.