Modulation of cytochrome P450 by 5,5'-bis-trifluoromethyl-2,2'-dichlorobiphenyl, a unique environmental contaminant.
5,5'-Bis-trifluoromethyl-2,2'-dichlorobiphenyl (5,5'CF3-2,2'PCB) is representative of a unique class of trifluoromethyl polychlorinated biphenyls (CF3-PCBs) found in sediments and fish of Lake Ontario, the Niagara river, and their tributaries. The potential hazard of 5,5'CF3-2,2'PCB was assessed by exposing male Wistar rats to this agent in corn oil at a dose of 1 mg/kg/day or 75 mg/kg/day or corn oil alone (control) by oral intubation for 7 consecutive days. No lethality occurred during the course of exposure. A significant increase in liver weight and liver/body weight ratio and significant decrease in body weight gain were observed following exposure to the high dose of CF3-PCB, relative to control. Exposure to the CF3-PCB also resulted in a dose-related increase in the total hepatic cytochrome P450 content. This was associated with a dose-related increase in the O-deethylation of ethoxycoumarin, an activity which is mediated by several cytochrome P450s and thus provides a general representation of cytochrome P450 status. Specifically, a dose-dependent induction of the cytochrome P450s 1A1 and 1A2 (CYP1A1 and CYP1A2) proteins and their respective activities was observed, with significant induction occurring in both the low and high dose CF3-PCB groups, compared to control. Additionally, CYP2B1 and CYP2B2 proteins and activities were induced following treatment with the high dose of 5,5'CF3-2,2'PCB. Since, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds selectively induce CYP1A1 and CYP1A2. the results suggest that 5,5'CF3-2,2'PCB has significant dioxin-like activity. Furthermore, 5,5'CF3-2,2'PCB appears to be acting as a mixed-type inducer since phenobarbital-like induction of CYP2B1 and 2B2 was also associated with exposure.
Drahushuk
A T
AT
Department of Pharmacology and Toxicology, SUNY at Buffalo, 14214, USA.
Choy
C O
CO
Kumar
S
S
McReynolds
J H
JH
Olson
J R
JR
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens / Q000633:toxicity*; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D019362:Cytochrome P-450 CYP2B1 / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015151:Immunoblotting; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D009929:Organ Size / Q000187:drug effects; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D013250:Steroid Hydroxylases / Q000378:metabolism
C107005:5,5'-bis-trifluoromethyl-2,2'-dichlorobiphenyl; D002273:Carcinogens; D000072317:Polychlorinated Dibenzodioxins; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D019362:Cytochrome P-450 CYP2B1; C025619:steroid 16-beta-hydroxylase