RGD Reference Report - 3-methylcholanthrene and benzo(a)pyrene modulate cardiac cytochrome P450 gene expression and arachidonic acid metabolism in male Sprague Dawley rats. - Rat Genome Database

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3-methylcholanthrene and benzo(a)pyrene modulate cardiac cytochrome P450 gene expression and arachidonic acid metabolism in male Sprague Dawley rats.

Authors: Aboutabl, Mona E  Zordoky, Beshay N M  El-Kadi, Ayman O S 
Citation: Aboutabl ME, etal., Br J Pharmacol. 2009 Dec;158(7):1808-19. doi: 10.1111/j.1476-5381.2009.00461.x.
RGD ID: 401794453
Pubmed: PMID:19889059   (View Abstract at PubMed)
PMCID: PMC2801222   (View Article at PubMed Central)
DOI: DOI:10.1111/j.1476-5381.2009.00461.x   (Journal Full-text)


BACKGROUND AND PURPOSE: There is a strong correlation between cytochrome P450 (P450)-dependent arachidonic acid metabolism and the pathogenesis of cardiac hypertrophy. Several aryl hydrocarbon receptor (AhR) ligands were found to alter P450-dependent arachidonic acid metabolism. Here, we have investigated the effect of 3-methylcholanthrene (3-MC) and benzo(a)pyrene (BaP), two AhR ligands, on the development of cardiac hypertrophy.
EXPERIMENTAL APPROACH: Male Sprague Dawley rats were injected (i.p.) daily with either 3-MC (10 mg kg(-1)) or BaP (20 mg kg(-1)) for 7 days. Then hearts were removed, and the heart to body weight ratio and the gene expression of the hypertrophic markers and P450 genes were determined. Levels of arachidonic acid metabolites were determined by liquid chromatography-electron spray ionization-mass spectrometry.
KEY RESULTS: Both 3-MC and BaP increased the heart to body weight ratio as well as the hypertrophic markers, atrial natriuretic peptide and brain natriuretic peptide. 3-MC and BaP treatment increased the gene expression of CYP1A1, CYP1B1, CYP2E1, CYP4F4, CYP4F5 and soluble epoxide hydrolase. Both 3-MC and BaP treatments increased the dihydroxyeicosatrienoic acids (DHETs) : epoxyeicosatrienoic acids (EETs) ratio and the 20-hydroxyeicosatetraenoic acid (20-HETE) : total EETs ratio. Treatment with benzo(e)pyrene, an isomer of BaP that is a poor ligand for the AhR, did not induce cardiac hypertrophy in rats, confirming the role of AhR in the development of cardiac hypertrophy. Treatment with the omega-hydroxylase inhibitor, HET0016, significantly reversed BaP-induced cardiac hypertrophy.
CONCLUSIONS AND IMPLICATIONS: 3-MC and BaP induce cardiac hypertrophy by increasing the ratio of DHETs : EETs and/or the ratio of 20-HETE : total EETs, through increasing soluble epoxide hydrolase activity.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
AHRHumanhypertrophic cardiomyopathy  ISOAhr (Rattus norvegicus) RGD 
AhrRathypertrophic cardiomyopathy  IMP  RGD 
AhrMousehypertrophic cardiomyopathy  ISOAhr (Rattus norvegicus) RGD 
CYP1A1Humanhypertrophic cardiomyopathy  ISOCyp1a1 (Rattus norvegicus)mRNA and protein:increased expression:heart (rat)RGD 
CYP1B1Humanhypertrophic cardiomyopathy  ISOCyp1b1 (Rattus norvegicus)mRNA and protein:increased expression:heart (rat)RGD 
CYP2E1Humanhypertrophic cardiomyopathy  ISOCyp2e1 (Rattus norvegicus)mRNA and protein:increased expression:heart (rat)RGD 
Cyp1a1Mousehypertrophic cardiomyopathy  ISOCyp1a1 (Rattus norvegicus)mRNA and protein:increased expression:heart (rat)RGD 
Cyp1a1Rathypertrophic cardiomyopathy  IEP mRNA and protein:increased expression:heart (rat)RGD 
Cyp1b1Mousehypertrophic cardiomyopathy  ISOCyp1b1 (Rattus norvegicus)mRNA and protein:increased expression:heart (rat)RGD 
Cyp1b1Rathypertrophic cardiomyopathy  IEP mRNA and protein:increased expression:heart (rat)RGD 
Cyp2e1Mousehypertrophic cardiomyopathy  ISOCyp2e1 (Rattus norvegicus)mRNA and protein:increased expression:heart (rat)RGD 
Cyp2e1Rathypertrophic cardiomyopathy  IEP mRNA and protein:increased expression:heart (rat)RGD 
Cyp4f4Rathypertrophic cardiomyopathy  IEP mRNA:increased expression:heart (rat)RGD 
Cyp4f5Rathypertrophic cardiomyopathy  IEP mRNA:increased expression:heart (rat)RGD 
EPHX2Humanhypertrophic cardiomyopathy  ISOEphx2 (Rattus norvegicus)mRNA and protein:increased expression:heart (rat)RGD 
Ephx2Mousehypertrophic cardiomyopathy  ISOEphx2 (Rattus norvegicus)mRNA and protein:increased expression:heart (rat)RGD 
Ephx2Rathypertrophic cardiomyopathy  IEP mRNA and protein:increased expression:heart (rat)RGD 
HMOX1Humanhypertrophic cardiomyopathy  ISOHmox1 (Rattus norvegicus)protein:increased activity:heart (rat)RGD 
Hmox1Rathypertrophic cardiomyopathy  IEP protein:increased activity:heart (rat)RGD 
Hmox1Mousehypertrophic cardiomyopathy  ISOHmox1 (Rattus norvegicus)protein:increased activity:heart (rat)RGD 
NPPAHumanhypertrophic cardiomyopathy  ISONppa (Rattus norvegicus)mRNA:increased expression:heart (rat)RGD 
NPPBHumanhypertrophic cardiomyopathy  ISONppb (Rattus norvegicus)mRNA:increased expression:heart (rat)RGD 
NppaMousehypertrophic cardiomyopathy  ISONppa (Rattus norvegicus)mRNA:increased expression:heart (rat)RGD 
NppaRathypertrophic cardiomyopathy  IEP mRNA:increased expression:heart (rat)RGD 
NppbRathypertrophic cardiomyopathy  IEP mRNA:increased expression:heart (rat)RGD 
NppbMousehypertrophic cardiomyopathy  ISONppb (Rattus norvegicus)mRNA:increased expression:heart (rat)RGD 

Gene-Chemical Interaction Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
CYP1A1Human3-methylcholanthrene increases expression ISOCyp1a1 (Rattus norvegicus)3-methylcholanthrene increases expression of mRNA and protein in rat heartRGD 
CYP1B1Human3-methylcholanthrene increases expression ISOCyp1b1 (Rattus norvegicus)3-methylcholanthrene increases expression of mRNA and protein in rat heartRGD 
CYP2E1Human3-methylcholanthrene increases expression ISOCyp2e1 (Rattus norvegicus)3-methylcholanthrene increases expression of mRNA and protein in rat heartRGD 
Cyp1a1Mouse3-methylcholanthrene increases expression ISOCyp1a1 (Rattus norvegicus)3-methylcholanthrene increases expression of mRNA and protein in rat heartRGD 
Cyp1a1Rat3-methylcholanthrene increases expression EXP 3-methylcholanthrene increases expression of mRNA and protein in rat heartRGD 
Cyp1b1Mouse3-methylcholanthrene increases expression ISOCyp1b1 (Rattus norvegicus)3-methylcholanthrene increases expression of mRNA and protein in rat heartRGD 
Cyp1b1Rat3-methylcholanthrene increases expression EXP 3-methylcholanthrene increases expression of mRNA and protein in rat heartRGD 
Cyp2e1Mouse3-methylcholanthrene increases expression ISOCyp2e1 (Rattus norvegicus)3-methylcholanthrene increases expression of mRNA and protein in rat heartRGD 
Cyp2e1Rat3-methylcholanthrene increases expression EXP 3-methylcholanthrene increases expression of mRNA and protein in rat heartRGD 
Cyp4a3Rat3-methylcholanthrene increases expression EXP 3-methylcholanthrene increases expression of mRNA in rat heartRGD 
Cyp4f4Rat3-methylcholanthrene increases expression EXP 3-methylcholanthrene increases expression of mRNA in rat heartRGD 
Cyp4f5Rat3-methylcholanthrene increases expression EXP 3-methylcholanthrene increases expression of mRNA in rat heartRGD 
EPHX2Human3-methylcholanthrene increases expression ISOEphx2 (Rattus norvegicus)3-methylcholanthrene increases expression of mRNA and protein in rat heartRGD 
Ephx2Mouse3-methylcholanthrene increases expression ISOEphx2 (Rattus norvegicus)3-methylcholanthrene increases expression of mRNA and protein in rat heartRGD 
Ephx2Rat3-methylcholanthrene increases expression EXP 3-methylcholanthrene increases expression of mRNA and protein in rat heartRGD 
NPPAHuman3-methylcholanthrene increases expression ISONppa (Rattus norvegicus)3-methylcholanthrene increases expression of mRNA in rat heartRGD 
NPPBHuman3-methylcholanthrene increases expression ISONppb (Rattus norvegicus)3-methylcholanthrene increases expression of mRNA in rat heartRGD 
NppaMouse3-methylcholanthrene increases expression ISONppa (Rattus norvegicus)3-methylcholanthrene increases expression of mRNA in rat heartRGD 
NppaRat3-methylcholanthrene increases expression EXP 3-methylcholanthrene increases expression of mRNA in rat heartRGD 
NppbRat3-methylcholanthrene increases expression EXP 3-methylcholanthrene increases expression of mRNA in rat heartRGD 
NppbMouse3-methylcholanthrene increases expression ISONppb (Rattus norvegicus)3-methylcholanthrene increases expression of mRNA in rat heartRGD 
CYP1A1Humanbenzo[a]pyrene increases expression ISOCyp1a1 (Rattus norvegicus)benzo[a]pyrene increases expression of mRNA and protein in rat heartRGD 
CYP1B1Humanbenzo[a]pyrene increases expression ISOCyp1b1 (Rattus norvegicus)benzo[a]pyrene increases expression of mRNA and protein in rat heartRGD 
CYP2E1Humanbenzo[a]pyrene increases expression ISOCyp2e1 (Rattus norvegicus)benzo[a]pyrene increases expression of mRNA and protein in rat heartRGD 
Cyp1a1Ratbenzo[a]pyrene increases expression EXP benzo[a]pyrene increases expression of mRNA and protein in rat heartRGD 
Cyp1a1Mousebenzo[a]pyrene increases expression ISOCyp1a1 (Rattus norvegicus)benzo[a]pyrene increases expression of mRNA and protein in rat heartRGD 
Cyp1b1Ratbenzo[a]pyrene increases expression EXP benzo[a]pyrene increases expression of mRNA and protein in rat heartRGD 
Cyp1b1Mousebenzo[a]pyrene increases expression ISOCyp1b1 (Rattus norvegicus)benzo[a]pyrene increases expression of mRNA and protein in rat heartRGD 
Cyp2e1Ratbenzo[a]pyrene increases expression EXP benzo[a]pyrene increases expression of mRNA and protein in rat heartRGD 
Cyp2e1Mousebenzo[a]pyrene increases expression ISOCyp2e1 (Rattus norvegicus)benzo[a]pyrene increases expression of mRNA and protein in rat heartRGD 
Cyp4f4Ratbenzo[a]pyrene increases expression EXP benzo[a]pyrene increases expression of mRNA in rat heartRGD 
Cyp4f5Ratbenzo[a]pyrene increases expression EXP benzo[a]pyrene increases expression of mRNA in rat heartRGD 
EPHX2Humanbenzo[a]pyrene increases expression ISOEphx2 (Rattus norvegicus)benzo[a]pyrene increases expression of mRNA and protein in rat heartRGD 
Ephx2Ratbenzo[a]pyrene increases expression EXP benzo[a]pyrene increases expression of mRNA and protein in rat heartRGD 
Ephx2Mousebenzo[a]pyrene increases expression ISOEphx2 (Rattus norvegicus)benzo[a]pyrene increases expression of mRNA and protein in rat heartRGD 
NPPAHumanbenzo[a]pyrene increases expression ISONppa (Rattus norvegicus)benzo[a]pyrene increases expression of mRNA in rat heartRGD 
NPPBHumanbenzo[a]pyrene increases expression ISONppb (Rattus norvegicus)benzo[a]pyrene increases expression of mRNA in rat heartRGD 
NppaRatbenzo[a]pyrene increases expression EXP benzo[a]pyrene increases expression of mRNA in rat heartRGD 
NppaMousebenzo[a]pyrene increases expression ISONppa (Rattus norvegicus)benzo[a]pyrene increases expression of mRNA in rat heartRGD 
NppbRatbenzo[a]pyrene increases expression EXP benzo[a]pyrene increases expression of mRNA in rat heartRGD 
NppbMousebenzo[a]pyrene increases expression ISONppb (Rattus norvegicus)benzo[a]pyrene increases expression of mRNA in rat heartRGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  

Molecular Function

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
AhrRatarachidonate omega-hydroxylase activity  IMP  RGD 
Hmox1Ratarachidonate omega-hydroxylase activity  IMP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Ahr  (aryl hydrocarbon receptor)
Cyp1a1  (cytochrome P450, family 1, subfamily a, polypeptide 1)
Cyp1b1  (cytochrome P450, family 1, subfamily b, polypeptide 1)
Cyp2e1  (cytochrome P450, family 2, subfamily e, polypeptide 1)
Cyp4a3  (cytochrome P450, family 4, subfamily a, polypeptide 3)
Cyp4f4  (cytochrome P450, family 4, subfamily f, polypeptide 4)
Cyp4f5  (cytochrome P450, family 4, subfamily f, polypeptide 5)
Ephx2  (epoxide hydrolase 2)
Hmox1  (heme oxygenase 1)
Nppa  (natriuretic peptide A)
Nppb  (natriuretic peptide B)

Genes (Mus musculus)
Ahr  (aryl-hydrocarbon receptor)
Cyp1a1  (cytochrome P450, family 1, subfamily a, polypeptide 1)
Cyp1b1  (cytochrome P450, family 1, subfamily b, polypeptide 1)
Cyp2e1  (cytochrome P450, family 2, subfamily e, polypeptide 1)
Ephx2  (epoxide hydrolase 2, cytoplasmic)
Hmox1  (heme oxygenase 1)
Nppa  (natriuretic peptide precursor type A)
Nppb  (natriuretic peptide type B)

Genes (Homo sapiens)
AHR  (aryl hydrocarbon receptor)
CYP1A1  (cytochrome P450 family 1 subfamily A member 1)
CYP1B1  (cytochrome P450 family 1 subfamily B member 1)
CYP2E1  (cytochrome P450 family 2 subfamily E member 1)
EPHX2  (epoxide hydrolase 2)
HMOX1  (heme oxygenase 1)
NPPA  (natriuretic peptide A)
NPPB  (natriuretic peptide B)


Additional Information