MARKED ENDOGENOUS ACTIVATION OF THE CYP1A1 AND CYP1A2 GENES IN THE CONGENITALLY JAUNDICED GUNN RAT

The homozygous recessive jaundiced Gunn rat lacks expression of biliru bin UDP-glucuronosyltransferase and serves as a model for Crigler-Najj ar syndrome type I, in which high and toxic plasma levels of bilirubin result from this genetic defect in bilirubin conjugation. Both rats a nd humans dispose of this heme waste product by an alternate metabolic route that involves oxidation of the compound, followed by biliary ex cretion of the more polar metabolites. To determine the role of cytoch rome P450 in this process, hepatic levels of cytochrome P450 mRNA and protein were measured in jaundiced and nonjaundiced Gunn rats as a fun ction of age and sex. The mRNA and protein levels of cytochrome P450(C YP) 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, indicati ng that the CYP1A P450 genes were specifically induced. CYP1A1 mRNA an d protein levels increased further in the jaundiced animals between 10 days and 1 month of Postnatal life but remained undetectable in the n onjaundiced littermates. On the other hand, CYP1A2 mRNA and protein co ntent increased during this time period in both jaundiced and nonjaund iced rats, but at the age of 1 month there were no major differences b etween the two groups. CYP1A2 mRNA and protein levels were indistingui shable in 3-month-old jaundiced and nonjaundiced Gunn rats, whereas CY P1A1 could not be detected in either group. These data suggest that yo ung jaundiced Gunn rats cope with the degradation of toxic bilirubin b y increasing hepatic levels of CYP1A1 and CYP1A2. On the other hand, n ormal developmental activation of CYP1A2 may provide the alternative p athway for bilirubin degradation in adult animals. This is the first d emonstration of the induction of cytochrome P450 gene expression to pe rmit the elimination of an endogenously generated neurotoxic chemical in a genetic disease in which the normal excretory mechanism is impair ed.