RGD Reference Report - Downregulation of intestinal cytochrome p450 in chronic renal failure. - Rat Genome Database

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Downregulation of intestinal cytochrome p450 in chronic renal failure.

Authors: Leblond, FA  Petrucci, M  Dube, P  Bernier, G  Bonnardeaux, A  Pichette, V 
Citation: Leblond FA, etal., J Am Soc Nephrol. 2002 Jun;13(6):1579-85.
RGD ID: 7296923
Pubmed: PMID:12039987   (View Abstract at PubMed)

Chronic renal failure (CRF) is associated with a decrease in intestinal drug metabolism. The mechanisms remain poorly understood, but one hypothesis involves a reduction in cytochrome P450 levels. This study aimed to investigate the effects of CRF on intestinal cytochrome P450. Two groups of rats were defined, i.e., rats with CRF (induced by 5/6 nephrectomy) and control pair-fed rats. Total cytochrome P450 levels and protein and mRNA expression of cytochrome P450 isoforms, as well as in vitro N-demethylation of erythromycin (a probe for CYP3A activity) and 7-ethoxyresorufin o-deethylase activity (a probe for CYP1A), were assessed in intestinal microsomes. Body weights were similar in the two groups. Creatinine clearance was reduced by 77% (P < 0.001) in CRF rats, compared with control pair-fed animals. Total intestinal cytochrome P450 activity was reduced by 32% (P < 0.001) in CRF rats. CYP1A1 and CYP3A2 protein expression was considerably reduced (>40%, P < 0.001) in rats with CRF. CYP2B1, CYP2C6, and CYP2C11 levels were the same in the two groups. RT-PCR assays revealed marked downregulation of CYP1A1 and CYP3A2 gene expression in CRF rats (P < 0.001). Although intestinal cytochrome P450 levels were reduced in CRF, induction by dexamethasone was present. N-Demethylation of erythromycin and 7-ethoxyresorufin o-deethylase activity were decreased by 25% (P < 0.05) in CRF rats, compared with control rats. In conclusion, CRF in rats is associated with decreases in intestinal cytochrome P450 activity (mainly CYP1A1 and CYP3A2) secondary to reduced gene expression.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
end stage renal disease  ISOCyp1a1 (Rattus norvegicus)7296923; 7296923mRNA and protein:decreased expression:intestineRGD 
end stage renal disease  ISOCyp3a2 (Rattus norvegicus)7296923mRNA and protein:decreased expression:intestineRGD 
end stage renal disease  IEP 7296923; 7296923mRNA and protein:decreased expression:intestineRGD 
end stage renal disease  ISOCYP3A4 (Homo sapiens)7296923mRNA and protein:decreased expression:intestineRGD 

Objects Annotated

Genes (Rattus norvegicus)
Cyp1a1  (cytochrome P450, family 1, subfamily a, polypeptide 1)
Cyp3a2  (cytochrome P450, family 3, subfamily a, polypeptide 2)

Genes (Mus musculus)
Cyp1a1  (cytochrome P450, family 1, subfamily a, polypeptide 1)
Cyp3a11  (cytochrome P450, family 3, subfamily a, polypeptide 11)

Genes (Homo sapiens)
CYP1A1  (cytochrome P450 family 1 subfamily A member 1)
CYP3A4  (cytochrome P450 family 3 subfamily A member 4)


Additional Information