Role of the aromatic hydrocarbon receptor in the suppression of cytochrome P-450 2C11 by polycyclic aromatic hydrocarbons.
The aromatic hydrocarbon (AH) receptor mediates the induction of cytochromes P-450 (CYP) of the CYP1A subfamily caused by polycyclic aromatic hydrocarbons (PAHs). CYP1A induction by PAHs is accompanied by down-regulation of CYP2C11, the predominant CYP expressed constitutively in the liver of male rats. We performed a structure-activity relationship study with a series of PAHs of the anthracene class in order to determine if the AH receptor is involved in CYP2C11 down-regulation. Anthracene, benz[a]anthracene, dibenz[a,c]anthracene, dibenz[a,h]anthracene, 7,12-dimethylbenz[a]anthracene, as well as 2,3,7,8-tetrachlorodibenzo-p-dioxin and 3-methylcholanthrene decreased CYP2C11 immunoreactive protein levels to varying degrees in primary rat hepatocytes cultured on a laminin-rich extracellular matrix. The binding affinity of the PAHs for the rat liver cytosolic AH receptor correlated with the potency for transforming the cytosolic AH receptor to its DNA-binding form. In addition, the ability of the PAHs to suppress CYP2C11 correlated with both the AH receptor binding affinity and the AH receptor transformation potency. These results suggest that the AH receptor plays a role in the down-regulation of CYP2C11 caused by PAHs.
Safa
B
B
Department of Pharmacology, University of Toronto, Ont., Canada.
Lee
C
C
Riddick
D S
DS
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D000072467:Cytochrome P450 Family 2; D004790:Enzyme Induction / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D011084:Polycyclic Aromatic Hydrocarbons / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects* / Q000502:physiology*; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D013329:Structure-Activity Relationship
D065607:Cytochrome P-450 Enzyme Inhibitors; D011084:Polycyclic Aromatic Hydrocarbons; D018336:Receptors, Aryl Hydrocarbon; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase