title: Subacute effects of the brominated flame retardants hexabromocyclododecane and tetrabromobisphenol A on hepatic cytochrome P450 levels in rats.
abstract: The brominated flame retardants tetrabromobisphenol A (TBBPA) and hexabromocyclododecane (HBCD) are found in the environment, e.g., in sediments and organisms, in food items, human blood samples and mother's milk. In this study, the effects of both compounds on rat hepatic cytochrome P450 (CYP) levels and activities were investigated. Juvenile/young male and female Wistar rats were treated orally with various doses via the feed (TBBPA) or by gavage (HBCD). After 28 days of treatment the animals were sacrificed and hepatic mRNA and microsomes were isolated. HBCD treatment led to a significant induction of CYP2B1 mRNA, CYP2B1/2B2 protein and 7-pentoxyresorufin O-depentylase (PROD) activity suggesting a phenobarbital-type of induction. Furthermore, a significant increase in CYP3A1/3A3 mRNA, CYP3A1 protein, and luciferin benzylether debenzylase (LBD) activity was found, being more pronounced in females than in males. The effect on CYP3A1/3A3 mRNA was significant in female rats at a daily dose of 3.0mg/kg body weight and above. HBCD exhibited no effects on CYP1A2 mRNA, CYP1A1/1A2 protein, or microsomal 7-ethoxyresorufin O-deethylase (EROD) activity suggesting lack of activation of the aryl hydrocarbon receptor. No significant effects on any of the parameters measured were obtained with TBBPA. Our findings suggest that oral exposure to HBCD induces drug-metabolising enzymes in rats probably via the CAR/PXR signalling pathway. Induction of CYPs and co-regulated enzymes of phase II of drug metabolism may affect homeostasis of endogenous substrates including steroid and thyroid hormones.
authors.affiliation: Food Chemistry and Environmental Toxicology, University of Kaiserslautern, D-67663 Kaiserslautern, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Germer
authors.forename: Aldert H
authors.initials: AH
authors.lastname: Piersma
authors.forename: Leo
authors.initials: L
authors.lastname: van der Ven
authors.forename: Andreas
authors.initials: A
authors.lastname: Kamyschnikow
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Fery
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Schmitz
authors.forename: Dieter
authors.initials: D
authors.lastname: Schrenk
mesh_terms: D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D005411:Flame Retardants / Q000633:toxicity*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006842:Hydrocarbons, Brominated / Q000633:toxicity*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D011075:Polybrominated Biphenyls / Q000633:toxicity; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D005411:Flame Retardants; D006842:Hydrocarbons, Brominated; D011075:Polybrominated Biphenyls; D012333:RNA, Messenger; C089796:hexabromocyclododecane; D003577:Cytochrome P-450 Enzyme System; C020806:tetrabromobisphenol A