Ten nucleotide differences, five of which cause amino acid changes, are associated with the Ah receptor locus polymorphism of C57BL/6 and DBA/2 mice

Chang, Ching‐yi; Smith, David Roy; Prasad, Vandna; Sidman, Charles L.; Nebert, Daniel W.; Puga, Alvaro

doi:10.1097/00008571-199312000-00005

Cited by 106 publications

(52 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Primary hepatocyte cultures derived from livers of DBA/2 and C57BL/6 mice were used to investigate the inducibility of the Cyp2a5 gene by TCDD. These mice show a well characterized, genetically determined differential response to AHR ligands; the DBA/2 mouse AHR having about 10-fold lower affinity to TCDD than that of the C57BL/6 mouse (Chang et al, 1993;Ema et al, 1994). The Cyp2a5 gene was found to be induced dose dependently by TCDD in both mouse strains, as determined by the mRNA levels ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Regulation of the Cyp2a5 Gene Involves an Aryl Hydrocarbon Receptor-Dependent Pathway

Arpiainen¹,

Raffalli-Mathieu²,

Lang³

et al. 2005

Molecular Pharmacology

View full text Add to dashboard Cite

We have investigated the role of the aryl hydrocarbon receptor (AHR) in the regulation of the Cyp2a5 gene. The C57BL/6 and DBA/2 mouse strains with a genetically determined difference in AHR function were used to study the CYP2A5 induction by typical AHR ligands, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 3-methylcholanthrene. The CYP2A5 mRNA upregulation in these mouse strains showed a difference in response, typical for AHR-regulated genes, both by TCDD in cultured primary hepatocytes and by 3-methylcholanthrene in vivo. In primary hepatocytes, TCDD caused a 3-fold elevation of the CYP2A5 protein level and a similar induction of the CYP2A5-catalyzed coumarin 7-hydroxylation activity. In reporter gene assays, the Cyp2a5 promoter region Ϫ3033 to ϩ10 mediated a 2-to 5-fold induction of luciferase activity by TCDD treatment in primary hepatocytes and in Hepa-1 hepatoma cells with an intact AHR/AHR nuclear translocator (ARNT) complex. In Hepa-1 variant cell lines with deficiencies in the AHR/ ARNT complex, the absence of ARNT abolished the induction. A putative AHR response element (XRE) was identified in the Cyp2a5 promoter at the position Ϫ2514 to Ϫ2492 and found to interact with the AHR/ARNT heterodimer. Transfection experiments combined with mutation of the XRE site indicated that the site partly mediates the TCDD induction of Cyp2a5. An additional AHR-dependent mechanism also regulates the proximal promoter of the Cyp2a5 gene. In conclusion, our studies showed that AHR ligands up-regulate Cyp2a5 transcriptionally by an AHR/ARNT-dependent mechanism and established Cyp2a5 as a novel AHR-regulated gene.The mouse cytochrome P450 CYP2A5 and its human ortholog CYP2A6 metabolize several toxic substances, such as nitrosamines and aflatoxins (Camus et al., 1993;Pelkonen et al., 1997b). In addition to hepatocytes, CYP2A5 and CYP2A6 are expressed in some extrahepatic tissues, especially nasal mucosa (Kaipainen and Lang, 1985;Su et al., 1996;Koskela et al., 1999). The regulation of CYP2A5 is complex and significantly different from that of the other major xenobioticmetabolizing P450 enzymes, and both transcriptional and post-transcriptional mechanisms seem to be essential (Glisovic et al., 2003b). Coumarin 7-hydroxylase (COH) activity, catalyzed predominantly by CYP2A5 and CYP2A6 (Pelkonen et al., 1997a), is inducible by a number of structurally diverse compounds, including phenobarbital, rifampicin, pyrazole, and its derivatives, as well as porphyrinogenic substances (Donato et al., 2000). In addition, CYP2A5 is elevated in mouse liver tumors (Kobliakov et al., 1993). A hepatotoxin pyrazole induces CYP2A5 by a post-transcriptional mechanism involving binding of heterogenous nuclear ribonucleoprotein A1 (hnRNP A1) to the 3Ј untranslated region of CYP2A5 mRNA, with subsequent stabilization of the mRNA (Glisovic et al., 2003a). Otherwise, the mechanisms behind CYP2A5 induction are still mainly unknown.The aryl hydrocarbon receptor (AHR) is a ligandactivated transcription factor involved in the regulation of seve...

show abstract

Section: Resultsmentioning

confidence: 99%

Regulation of the Cyp2a5 Gene Involves an Aryl Hydrocarbon Receptor-Dependent Pathway

Arpiainen¹,

Raffalli-Mathieu²,

Lang³

et al. 2005

Molecular Pharmacology

View full text Add to dashboard Cite

show abstract

“…The four identified mouse alleles differ by 8 nucleotides in their shared open reading frame. In addition, these AHRs differ by 45 amino acids at their C-terminus as a result of a nucleotide change in the Ahr d allele that replaces the stop codon in the Ahr b allele with an arginine (Chang et al, 1993;Poland et al, 1994). Most of the amino acid changes distinguishing these strains occur within the transactivation domain and have little or no known functional consequence (Chang et al, 1993).…”

Section: Functional Alterations Of the Ahrmentioning

confidence: 99%

Induction of Oxidative Stress Responses by Dioxin and other Ligands of the Aryl Hydrocarbon Receptor

et al. 2005

Self Cite

View full text Add to dashboard Cite

ᮀTCDD and other polyhalogenated aromatic hydrocarbon ligands of the aryl hydrocarbon receptor (AHR) have been classically considered as non-genotoxic compounds because they fail to be directly mutagenic in either bacteria or most in vitro assay systems. They do so in spite of having repeatedly been linked to oxidative stress and to mutagenic and carcinogenic outcomes. Oxidative stress, on the other hand, has been used as a marker for the toxicity of dioxin and its congeners. We have focused this review on the connection between oxidative stress induction and the toxic effects of fetal and adult dioxin exposure, with emphasis on the large species difference in sensitivity to this agent. We examine the roles that the dioxin-inducible cytochromes P450s play in the cellular and toxicological consequences of dioxin exposure with emphasis on oxidative stress involvement. Many components of the health consequences resulting from dioxin exposure may be attributable to epigenetic mechanisms arising from prolonged reactive oxygen generation.

show abstract

“…The AhrbJ1 allele occurs in C57, C58, and MA/My inbred strains; the Ahtb-2 allele is carried by the C3H, BALB/cBy, and A inbred strains; the Ahr'-3 allele exists in Mus caroli, Mus spretus, and MOLF/Ei; and the AhAd allele occurs in AKR, DBA/2, and 129 strains (9). Ahr nucleotide differences, and corresponding AHR amino-acid changes between the C57BL/6 (B6) and DBA/2 (D2) mouse strains that carry the AhA'-1 and Ahkd alleles, respectively, have been studied extensively (9)(10)(11)(12)(13)(14)(15)). An A375V change has been reported to confer most of the observed phenotypic differences between B6 and D2 (15).…”

mentioning

confidence: 99%

“…Among the B6, D2, C3H, and Mus spretus mouse lines, there are 12 AHR amino acid differences (9)(10)(11)(12)(13)(14)(15). While most amino acid changes were shown to contribute greater than twofold to receptor affinity, the opal mutation contributes two-to threefold, and the A375V change contributes four-to sixfold to the differences in AHR affinity (9,15).…”

mentioning

confidence: 99%

Aromatic Hydrocarbon Receptor Polymorphism: Development of New Methods to Correlate Genotype with Phenotype

Maier¹,

Micka²,

Miller³

et al. 1998

Environmental Health Perspectives

Self Cite

View full text Add to dashboard Cite

Differential CYPlAl inducibility, reflecting variations in aromatic hydrocarbon receptor (AHR) affinity among inbred mouse strains, is an important determinant of environmental toxicity. We took advantage of the Air polymorphism in C57BL16 and DBA/2 mice to develop an oligonudeotide-hybridization screening approach for the rapid identification of DNA sequence differences between Air alleles. Oligonudeotides containing single-base changes at polymorphic sites were immobilized on a solid support and hybridized with C57BL/6 or DBA/2 AHR cDNA radiolabeled probes. The observed hybridization patterns demonstrate that this approach can be used to detect nudeotide differences in the Air coding region with very high accuracy. In parallel experiments, we used a yeast two-hybrid system to assess phenotypic differences in AHR function. AHR activation, as measured by 13-galactosidase reporter activity in Saceharomyces cerevisiae strain SFY526, was determined following treatment with varying doses of the AHR ligand P-naphthoflavone (BNF (9). Ahr nucleotide differences, and corresponding AHR amino-acid changes between the C57BL/6 (B6) and DBA/2 (D2) mouse strains that carry the AhA'-1 and Ahkd alleles, respectively, have been studied extensively (9-15). An A375V change has been reported to confer most of the observed phenotypic differences between B6 and D2 (15). With hepatic cytosol from B6 and D2 mice, ligand-affinity differences were found to range between 4-and 10-fold for the B6 and D2 AHRs (1618, whereas ligand-affinity differences range between 2-and 6-fold for the B6 and D2 AHRs when cDNA-expressed AHRs are studied (9,15 (15,22,

show abstract

Ten nucleotide differences, five of which cause amino acid changes, are associated with the Ah receptor locus polymorphism of C57BL/6 and DBA/2 mice

Cited by 106 publications

References 0 publications

Regulation of the Cyp2a5 Gene Involves an Aryl Hydrocarbon Receptor-Dependent Pathway

Regulation of the Cyp2a5 Gene Involves an Aryl Hydrocarbon Receptor-Dependent Pathway

Induction of Oxidative Stress Responses by Dioxin and other Ligands of the Aryl Hydrocarbon Receptor

Aromatic Hydrocarbon Receptor Polymorphism: Development of New Methods to Correlate Genotype with Phenotype

Contact Info

Product

Resources

About