RGD Reference Report - Marked endogenous activation of the CYP1A1 and CYP1A2 genes in the congenitally jaundiced Gunn rat. - Rat Genome Database

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Marked endogenous activation of the CYP1A1 and CYP1A2 genes in the congenitally jaundiced Gunn rat.

Authors: Kapitulnik, J  Gonzalez, F J 
Citation: Kapitulnik J and Gonzalez FJ, Mol Pharmacol. 1993 May;43(5):722-5.
RGD ID: 11576308
Pubmed: PMID:8502229   (View Abstract at PubMed)

The homozygous recessive jaundiced Gunn rat lacks expression of bilirubin UDP-glucuronosyltransferase and serves as a model for Crigler-Najjar syndrome type I, in which high and toxic plasma levels of bilirubin result from this genetic defect in bilirubin conjugation. Both rats and humans dispose of this heme waste product by an alternate metabolic route that involves oxidation of the compound, followed by biliary excretion of the more polar metabolites. To determine the role of cytochrome P450 in this process, hepatic levels of cytochrome P450 mRNA and protein were measured in jaundiced and nonjaundiced Gunn rats as a function of age and sex. The mRNA and protein levels of cytochrome P450(CYP) 1A1 and CYP1A2 were markedly elevated in the jaundiced rats at the age of 10 days, compared with their nonjaundiced littermates. Levels of CYP2E1 mRNA and protein did not differ between these rats, indicating that the CYP1A P450 genes were specifically induced. CYP1A1 mRNA and protein levels increased further in the jaundiced animals between 10 days and 1 month of postnatal life but remained undetectable in the nonjaundiced littermates. On the other hand, CYP1A2 mRNA and protein content increased during this time period in both jaundiced and nonjaundiced rats, but at the age of 1 month there were no major differences between the two groups. CYP1A2 mRNA and protein levels were indistinguishable in 3-month-old jaundiced and nonjaundiced Gunn rats, whereas CYP1A1 could not be detected in either group. These data suggest that young jaundiced Gunn rats cope with the degradation of toxic bilirubin by increasing hepatic levels of CYP1A1 and CYP1A2. On the other hand, normal developmental activation of CYP1A2 may provide the alternative pathway for bilirubin degradation in adult animals. This is the first demonstration of the induction of cytochrome P450 gene expression to permit the elimination of an endogenously generated neurotoxic chemical in a genetic disease in which the normal excretory mechanism is impaired.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
CYP1A1HumanJaundice  ISOCyp1a1 (Rattus norvegicus) RGD 
CYP1A2HumanJaundice  ISOCyp1a2 (Rattus norvegicus) RGD 
Cyp1a1RatJaundice  IEP  RGD 
Cyp1a1MouseJaundice  ISOCyp1a1 (Rattus norvegicus) RGD 
Cyp1a2RatJaundice  IEP  RGD 
Cyp1a2MouseJaundice  ISOCyp1a2 (Rattus norvegicus) RGD 
Gunn ratsRatJaundice MODEL: spontaneousIAGP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Cyp1a1  (cytochrome P450, family 1, subfamily a, polypeptide 1)
Cyp1a2  (cytochrome P450, family 1, subfamily a, polypeptide 2)

Genes (Mus musculus)
Cyp1a1  (cytochrome P450, family 1, subfamily a, polypeptide 1)
Cyp1a2  (cytochrome P450, family 1, subfamily a, polypeptide 2)

Genes (Homo sapiens)
CYP1A1  (cytochrome P450 family 1 subfamily A member 1)
CYP1A2  (cytochrome P450 family 1 subfamily A member 2)

Strains
Gunn rats  (NA)


Additional Information