The environmental pollutant 1,1-dichloro-2,2-bis (p-chlorophenyl)ethylene induces rat hepatic cytochrome P450 2B and 3A expression through the constitutive androstane receptor and pregnane X receptor.
1,1-Dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE), a persistent environmental contaminant, is a metabolite of the pesticide 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT). DDE is similar to phenobarbital (PB) in that both compounds are inducers of rat hepatic cytochrome P450 2B and 3A (CYP 2B and 3A). The induction of CYP 2B and 3A by PB is known to be regulated through the nuclear receptors constitutive androstane receptor (CAR) and pregnane X receptor (PXR), respectively. In the current study, the induction of hepatic CYP 3A1 and 2B1 by DDE was correlated with CAR and PXR activity. Induction of 3A1 and 2B1 was observed in the livers of adult and developing male Sprague-Dawley rats following exposure to DDE. Increased hepatic expression of 3A1, but not 2B1, in developing rats exposed during gestation and lactation persisted into adulthood. In receptor transactivation assays, both CAR and PXR transcriptional activities were significantly enhanced by DDE. Nuclear accumulation of CAR, but not PXR, was observed in the liver tissue following DDE and PB treatment. These data support the idea that induction of hepatic 3A1 and 2B1 by DDE is mediated through the activation of CAR and PXR. This study suggests that regulation by environmental compounds of hepatic enzymes via CAR and PXR may have impact on the metabolism of endogenous and exogenous substrates.
Wyde
Michael E
ME
CIIT Centers for Health Research, Research Triangle Park, North Carolina, USA.
Bartolucci
Erika
E
Ueda
Akiko
A
Zhang
He
H
Yan
Binfang
B
Negishi
Masahiko
M
You
Li
L
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D000090702:Constitutive Androstane Receptor; D019362:Cytochrome P-450 CYP2B1 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003633:Dichlorodiphenyl Dichloroethylene / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004785:Environmental Pollutants / Q000494:pharmacology*; D005260:Female; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D000077297:Pregnane X Receptor; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011987:Receptors, Steroid / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
D000090702:Constitutive Androstane Receptor; D004785:Environmental Pollutants; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; D003633:Dichlorodiphenyl Dichloroethylene; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D019362:Cytochrome P-450 CYP2B1; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating