title: Induction and suppression of cytochrome P450 1A by 3,3',4,4',5-pentachlorobiphenyl and its relationship to oxidative stress in the marine fish scup (Stenotomus chrysops).
abstract: The planar polychlorinated biphenyl (PCB) 3,3',4,4'-tetrachlorobiphenyl (TCB) causes dose-dependent induction and post-transcriptional suppression of hepatic cytochrome P450 1A (CYP1A) in the marine teleost scup (Stenotomus chrysops). That suppression is linked to inhibition and oxidative inactivation of CYP1A by TCB. Other planar PCBs, including 3,3',4,4',5-pentachlorobiphenyl (PeCB), inactivate scup CYP1A in vitro leading us to hypothesize that PeCB also will suppress CYP1A in vivo. We examined induction and suppression of CYP1A by PeCB in scup, as related to oxidative stress. PeCB at a low dose (0.01 mg/kg) induced hepatic microsomal spectral P450 and CYP1A protein and catalytic activities (ethoxyresorufin o-deethylase (EROD) and methoxyresorufin o-demethylase (MROD)) over an 18 day period. A high dose (1 mg PeCB/kg) only minimally induced hepatic spectral P450 and CYP1A content, and EROD and MROD rates remained at control levels at all sampling times, while CYP1A mRNA expression was induced strongly (up to 35-fold) at both doses. High dose PeCB had minimal effects on content of P450A (a CYP3A protein), P450B (a CYP2B-like protein) and cytochrome b5 in scup liver, suggesting that the suppression was specific for CYP1A. High dose PeCB suppressed EROD but not CYP1A protein in the kidney but did not strongly suppress either CYP1A or EROD in the heart or gill. PeCB stimulated ROS production (oxidation of dihydroethidium) by liver microsomes from the low dose but not the high dose fish, and the rate of PeCB-stimulated ROS production was correlated with EROD activity (r(2)=0.641, P<0.0005). Oxidative stress, indicated by increased levels of catalase, glutathione peroxidase, glutathione reductase and superoxide dismutase activities, was stimulated in the liver by low dose but not high dose PeCB. The results support a hypothesis that many PHAH can inactivate teleost CYP1A in vivo, and that CYP1A is a source of ROS. However, there appears to be a complex balance between the effects of PeCB on the levels of active CYP1A, ROS release and oxidative stress.
authors.affiliation: Biology Department, Woods Hole Oceanographic Institution, Redfield 342, MS 32, Woods Hole, MA 02543, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Schlezinger
authors.forename: J J
authors.initials: JJ
authors.lastname: Stegeman
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis*; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D008099:Liver / Q000201:enzymology; D018384:Oxidative Stress / Q000187:drug effects*; D010088:Oxidoreductases / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D010473:Perciformes / Q000378:metabolism*; D011078:Polychlorinated Biphenyls / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D065609:Cytochrome P-450 CYP1A2 Inhibitors; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; D010088:Oxidoreductases; C076307:methoxyresorufin-O-demethylase; D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; C023035:3,4,5,3',4'-pentachlorobiphenyl