Induction of the hepatic cytochrome P450 2B subfamily by xenobiotics: research history, evolutionary aspect, relation to tumorigenesis, and mechanism. 2006

Hideyuki Yamada, and Yuji Ishii, and Midori Yamamoto, and Kazuta Oguri
Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. yamada@xenoba.phar.kyushu-u.ac.jp

The cytochrome P450 belonging to the CYP2B subfamily has long been of great interest because it can be induced by xenobiotics. While a well known diagnostic ligand-receptor theory explains the induction of the CYP1A subfamily, the mechanism by which xenobiotics induce the CYP2B subfamily is not fully understood. Although the constitutive androstane receptor (CAR) undoubtedly plays a crucial role in the induction, many questions regarding the mechanism of CAR activation by xenobiotics have not yet been answered. It is a puzzle that many structurally-unrelated chemicals can increase the expression of the CYP2B subfamily. This may support a mechanism(s) distinct from the signaling induced by ligand-receptor binding. Indeed, phenobarbital, a typical inducer, cannot associate with CAR. Thus, no one is able to answer a fundamental question: what is the initial target of xenobiotics to produce induced expression of CYP2B enzymes? In this review, we survey the research history of CYP2B induction, list the inducers reported so far, and discuss the mechanism of induction including the target site of inducers.

UI MeSH Term Description Entries
D009369 Neoplasms New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms. Benign Neoplasm,Cancer,Malignant Neoplasm,Tumor,Tumors,Benign Neoplasms,Malignancy,Malignant Neoplasms,Neoplasia,Neoplasm,Neoplasms, Benign,Cancers,Malignancies,Neoplasias,Neoplasm, Benign,Neoplasm, Malignant,Neoplasms, Malignant
D010634 Phenobarbital A barbituric acid derivative that acts as a nonselective central nervous system depressant. It potentiates GAMMA-AMINOBUTYRIC ACID action on GABA-A RECEPTORS, and modulates chloride currents through receptor channels. It also inhibits glutamate induced depolarizations. Phenemal,Phenobarbitone,Phenylbarbital,Gardenal,Hysteps,Luminal,Phenobarbital Sodium,Phenobarbital, Monosodium Salt,Phenylethylbarbituric Acid,Acid, Phenylethylbarbituric,Monosodium Salt Phenobarbital,Sodium, Phenobarbital
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
D000090702 Constitutive Androstane Receptor A member of the nuclear receptor superfamily (subfamily 1, group I, member 3 [NR1i3]) involved, along with PREGNANE X RECEPTOR, in regulation of cellular responses to the exogenous and endogenous chemicals such as detoxification of XENOBIOTICS. CAR Nuclear Receptor,CAR Orphan Nuclear Receptor,Constitutive Active Receptor,Constitutive Androstane Receptor beta,Active Receptor, Constitutive,Androstane Receptor, Constitutive,Nuclear Receptor, CAR,Receptor, CAR Nuclear,Receptor, Constitutive Active
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
D014157 Transcription Factors Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. Transcription Factor,Factor, Transcription,Factors, Transcription
D015262 Xenobiotics Chemical substances that are foreign to the biological system. They include naturally occurring compounds, drugs, environmental agents, carcinogens, insecticides, etc. Xenobiotic
D018160 Receptors, Cytoplasmic and Nuclear Intracellular receptors that can be found in the cytoplasm or in the nucleus. They bind to extracellular signaling molecules that migrate through or are transported across the CELL MEMBRANE. Many members of this class of receptors occur in the cytoplasm and are transported to the CELL NUCLEUS upon ligand-binding where they signal via DNA-binding and transcription regulation. Also included in this category are receptors found on INTRACELLULAR MEMBRANES that act via mechanisms similar to CELL SURFACE RECEPTORS. Cytoplasmic Receptor,Cytoplasmic and Nuclear Receptors,Cytosolic and Nuclear Receptors,Hormone Receptors, Cytoplasmic,Hormone Receptors, Nuclear,Nuclear Hormone Receptor,Nuclear Receptor,Nuclear and Cytoplasmic Receptors,Cytoplasmic Hormone Receptors,Cytoplasmic Receptors,Cytosol and Nuclear Receptors,Intracellular Membrane Receptors,Nuclear Hormone Receptors,Nuclear Receptors,Receptors, Cytoplasmic,Receptors, Cytosol and Nuclear,Receptors, Cytosolic and Nuclear,Receptors, Intracellular Membrane,Receptors, Nuclear,Receptors, Nuclear and Cytoplasmic,Hormone Receptor, Nuclear,Membrane Receptors, Intracellular,Receptor, Cytoplasmic,Receptor, Nuclear,Receptor, Nuclear Hormone,Receptors, Cytoplasmic Hormone,Receptors, Nuclear Hormone

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