Biomaterial Database

Role of the aromatic hydrocarbon receptor in the suppression of cytochrome P-450 2C11 by polycyclic aromatic hydrocarbons. 1997

B Safa, and C Lee, and D S Riddick

Department of Pharmacology, University of Toronto, Ont., Canada.

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.

UI	MeSH Term	Description	Entries
D008099	Liver	A large lobed glandular organ in the abdomen of vertebrates that is responsible for detoxification, metabolism, synthesis and storage of various substances.	Livers
D008297	Male		Males
D011084	Polycyclic Aromatic Hydrocarbons	Aromatic hydrocarbons that contain extended fused-ring structures.	Polycyclic Aromatic Hydrocarbon,Polycyclic Hydrocarbons, Aromatic,Polynuclear Aromatic Hydrocarbon,Polynuclear Aromatic Hydrocarbons,Aromatic Hydrocarbon, Polycyclic,Aromatic Hydrocarbon, Polynuclear,Aromatic Hydrocarbons, Polycyclic,Aromatic Hydrocarbons, Polynuclear,Aromatic Polycyclic Hydrocarbons,Hydrocarbon, Polycyclic Aromatic,Hydrocarbon, Polynuclear Aromatic,Hydrocarbons, Aromatic Polycyclic,Hydrocarbons, Polycyclic Aromatic,Hydrocarbons, Polynuclear Aromatic
D003577	Cytochrome P-450 Enzyme System	A superfamily of hundreds of closely related HEMEPROTEINS found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (MIXED FUNCTION OXYGENASES). In animals, these P-450 enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (BIOTRANSFORMATION). They are classified, according to their sequence similarities rather than functions, into CYP gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the CYP1, CYP2, and CYP3 gene families are responsible for most drug metabolism.	Cytochrome P-450,Cytochrome P-450 Enzyme,Cytochrome P-450-Dependent Monooxygenase,P-450 Enzyme,P450 Enzyme,CYP450 Family,CYP450 Superfamily,Cytochrome P-450 Enzymes,Cytochrome P-450 Families,Cytochrome P-450 Monooxygenase,Cytochrome P-450 Oxygenase,Cytochrome P-450 Superfamily,Cytochrome P450,Cytochrome P450 Superfamily,Cytochrome p450 Families,P-450 Enzymes,P450 Enzymes,Cytochrome P 450,Cytochrome P 450 Dependent Monooxygenase,Cytochrome P 450 Enzyme,Cytochrome P 450 Enzyme System,Cytochrome P 450 Enzymes,Cytochrome P 450 Families,Cytochrome P 450 Monooxygenase,Cytochrome P 450 Oxygenase,Cytochrome P 450 Superfamily,Enzyme, Cytochrome P-450,Enzyme, P-450,Enzyme, P450,Enzymes, Cytochrome P-450,Enzymes, P-450,Enzymes, P450,Monooxygenase, Cytochrome P-450,Monooxygenase, Cytochrome P-450-Dependent,P 450 Enzyme,P 450 Enzymes,P-450 Enzyme, Cytochrome,P-450 Enzymes, Cytochrome,Superfamily, CYP450,Superfamily, Cytochrome P-450,Superfamily, Cytochrome P450
D004790	Enzyme Induction	An increase in the rate of synthesis of an enzyme due to the presence of an inducer which acts to derepress the gene responsible for enzyme synthesis.	Induction, Enzyme
D000072467	Cytochrome P450 Family 2	A cytochrome P450 enzyme family that includes members which function in the metabolism of STEROIDS; COUMARINS; and NICOTINE.	CYP2 Enzymes,CYP2 Family
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D001189	Aryl Hydrocarbon Hydroxylases	A large group of cytochrome P-450 (heme-thiolate) monooxygenases that complex with NAD(P)H-FLAVIN OXIDOREDUCTASE in numerous mixed-function oxidations of aromatic compounds. They catalyze hydroxylation of a broad spectrum of substrates and are important in the metabolism of steroids, drugs, and toxins such as PHENOBARBITAL, carcinogens, and insecticides.	Microsomal Monooxygenases,Xenobiotic Monooxygenases,Hydroxylases, Aryl Hydrocarbon,Monooxygenases, Microsomal,Monooxygenases, Xenobiotic
D013250	Steroid Hydroxylases	Cytochrome P-450 monooxygenases (MIXED FUNCTION OXYGENASES) that are important in steroid biosynthesis and metabolism.	Steroid Hydroxylase,Steroid Monooxygenases,Hydroxylase, Steroid,Hydroxylases, Steroid,Monooxygenases, Steroid
D013329	Structure-Activity Relationship	The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups.	Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships