Receptor-Mediated Gene Delivery Approach Demonstrates the Role of 5′-Proximal DNA Region in Conferring Phenobarbitone Responsiveness to CYP2B2 Gene in Rat Liver in Vivo

Mani, Sendurai A.; Srinivasan, Harish; Vathsala, P G; Rangarajan, Pundi N.; Padmanaban, Govindarajan

doi:10.1006/bbrc.2000.2203

Cited by 9 publications

(3 citation statements)

References 20 publications

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“…In the early 1990s, He and Fluco proposed for the first time a consensus sequence designated as "Barbie box" present at the promoter region of the PBinducible gene (upstream around -300 bp), and showed that PB alters the binding of regulatory protein to this region [142]. Since then another group has also supported this result [143,144], and it appears that the Barbie box plays a crucial role in the PB-mediated stimulation of gene expression. However, Ramsden et al have demonstrated from an experiment involving mice carrying the transgene of the CYP2B2 regulatory region that the PB-responsive ciselement is located in the distal region between -800 bp and -20kbp of the CYP2B2 gene [145].…”

Section: Xenobiotic Regulation Of Cyp2b Expre-ssionmentioning

confidence: 99%

Induction of the Hepatic Cytochrome P450 2B Subfamily by Xenobiotics: Research History, Evolutionary Aspect, Relation to Tumorigenesis, and Mechanism

Yamada

Ishii²,

Yamamoto

et al. 2006

CDM

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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.

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Section: Xenobiotic Regulation Of Cyp2b Expre-ssionmentioning

confidence: 99%

Induction of the Hepatic Cytochrome P450 2B Subfamily by Xenobiotics: Research History, Evolutionary Aspect, Relation to Tumorigenesis, and Mechanism

Yamada

Ishii²,

Yamamoto

et al. 2006

CDM

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“…This observation suggested a role of other region(s), distinct from the PBREM, that may also participate in the PB induction process. In this respect, several non-PBREM regions, such as RBP-J/NFB, have been suggested to be involved in the regulation of CYP2B gene expression [12,13]. Further studies are needed to better elucidate the basis of these alternative regulatory schemes.…”

Section: Introductionmentioning

confidence: 99%

Comparison of genomic and cDNA sequences of guinea pig CYP2B18 and rat CYP2B2: Absence of a phenobarbital‐responsive enhancer module in the upstream region of the CYP2B18 gene

Yamamoto

Mise

Matsumoto

et al. 2004

J Biochem & Molecular Tox

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Potential mechanisms were investigated whereby CYP2B18, a cytochrome P450 gene exhibiting high constitutive expression but only low levels of phenobarbital-inducibility in the guinea pig liver, may be differentially regulated versus the highly inducible rat CYP2B2 gene. To comparatively assess potential regulatory sequences associated with CYP2B18, a guinea pig genomic library was screened enabling isolation of the CYP2B18 gene. The genomic screening process resulted in the identification of at least four closely-related CYP2B18 genes, designated here as CYP2B18A-D. Of these isolates, CYP2B18A exhibited sequence identical to that of the CYP2B18 cDNA. Further, the deduced amino acid sequence of the CYP2B18 cDNA was identical to that of N-terminal and internally-derived peptide sequences obtained in this investigation from CYP2B18 protein isolated from guinea pig liver. Genomic structural sequences were derived for CYP2B18A, together with the respective 5'-upstream and intronic regions of the gene. Comparison of the CYP2B18A and CYP2B2 gene sequences revealed the lack of repetitive LINE gene sequences in CYP2B18A, putative silencing elements that effect neighboring genes, although these sequences were present in both 5'-upstream and 3'-downstream regions of CYP2B2. We determined that the phenobarbital-responsive enhancer module was absent from the 5'-upstream region as well as the intronic regions of CYP2B18A gene. We hypothesize that the compromised phenobarbital inducibility of CYP2B18A stems from its lack of a functional phenobarbital responsive enhancer module.

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“…As barbie boxes have been identified in each gene and that four of these are in common, differences in the level of response to PB could be due to barbie box quantity but also to the putative presence of PB response enhancer module (PBREM) which can be located in the distal part of the promotor (not sequenced in the present study) and also known to respond specifically to PB and various other PB-type inducers (Grigorieva et al, 2002). However, striking evidence of the role of the proximal promotor and of barbie boxes in induction of Cyp2b2 from rat by PB-like molecules was shown (Mani et al, 2000). Recently, Rencurel et al (2005) have shown in human that PB, via the cAMP signaling pathway, activates constitutive androstane receptors (CAR) which consequently bind with the PBREM site, and are thus responsible for activating increases in P450 expression.…”

Section: Discussionmentioning

confidence: 54%

Very high conservation between Cyp6a2 from Drosophila melanogaster and its ortholog Cyp6a26 from D. simulans

Tarès¹,

Arthaud²,

Brun‐Barale³

et al. 2007

Insect Science

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Although Drosophila simulans is closely related to D. melanogaster, very few cytochrome P450 genes have been studied in this species until now. As Cyp6a2 from D. melanogaster is a major gene implicated in the detoxification of xenobiotic molecules, we decided to look for its ortholog in D. simulans. The isolated gene, Cyp6a26, presents structural characteristics very similar to those of Cyp6a2: an identical size of 1 590‐bp comprising two exons separated by a 69‐bp intron and a nucleotide sequence homology of 95%. Many putative transcriptionally important motifs were identified in the upstream DNAs of the two genes but only 16 elements are in common positions. Treatment of flies with phenobarbital leads to an increased production of Cyp6a26 mRNAs. The expression of Cyp6a26 mRNAs varies following developmental stages in the same manner as Cyp6a2. Immunohistochemistry experiments of phenobarbital‐treated adult drosophila show that the spatial expression pattern of the two proteins is also conserved between the two species. All these data argue in favor of the conservation of the function of these homologous genes between the two Drosophila species.

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Receptor-Mediated Gene Delivery Approach Demonstrates the Role of 5′-Proximal DNA Region in Conferring Phenobarbitone Responsiveness to CYP2B2 Gene in Rat Liver in Vivo

Cited by 9 publications

References 20 publications

Induction of the Hepatic Cytochrome P450 2B Subfamily by Xenobiotics: Research History, Evolutionary Aspect, Relation to Tumorigenesis, and Mechanism

Induction of the Hepatic Cytochrome P450 2B Subfamily by Xenobiotics: Research History, Evolutionary Aspect, Relation to Tumorigenesis, and Mechanism

Comparison of genomic and cDNA sequences of guinea pig CYP2B18 and rat CYP2B2: Absence of a phenobarbital‐responsive enhancer module in the upstream region of the CYP2B18 gene

Very high conservation between Cyp6a2 from Drosophila melanogaster and its ortholog Cyp6a26 from D. simulans

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