J. Kapitulnik et Fj. Gonzalez, MARKED ENDOGENOUS ACTIVATION OF THE CYP1A1 AND CYP1A2 GENES IN THE CONGENITALLY JAUNDICED GUNN RAT, Molecular pharmacology, 43(5), 1993, pp. 722-725
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.