We have recently reported that disease-specific differential alterations in the hepatic expression of
xenobiotic-metabolizing
cytochrome P450 (CYP
P450) enzymes occur in patients with advanced
liver disease. In order to determine whether the observed changes in CYP
proteins are modulated at pre- or post-translational levels, we have now examined the hepatic levels of
mRNA for CYPs 1A2, 2C9, 2E1 and 3A4 by
solution hybridization in the same livers of 20 controls (surgical waste from histologically normal livers), 32 cases of hepatocellular and 18 of cholestatic severe chronic
liver disease.
CYP1A2 mRNA and CYP1A immunoreactive
protein were both reduced in livers with hepatocellular and cholestatic types of
cirrhosis. In contrast,
CYP3A4 mRNA and
protein were reduced only in livers from patients with hepatocellular diseases. For 1A2 and 3A4 there were significant correlations between
mRNA species and the respective
protein contents (rS1A2 = 0.74, rS3A4 = 0.64, P < 0.0001).
CYP2C9 mRNA was reduced in patients with both cholestatic and hepatocellular types of
liver disease, but 2C
protein was reduced only in patients with cholestatic dysfunction. The correlation between
CYP2C9 mRNA and
protein, was also significant (rs = 0.36, P < 0.005) but
mRNA levels accounted for only 13% of the variability in
protein rankings. This is probably a consequence of other
CYP2C proteins apart from 2C9 being detected by the anti-2C antibody.
CYP2E1 mRNA and
protein were reduced in patients with cholestatic
liver disease, but in hepatocellular disease the expression of only
CYP2E1 mRNA was decreased.
CYP2E1 mRNA was significantly correlated with
CYP2E1 protein but accounted for only 18% of the variability in
protein rankings (rs = 0.43, P < 0.0005). Taken collectively these data indicate that the disease-specific alterations of
xenobiotic-metabolizing CYP
enzymes among patients with
cirrhosis is due, at least in part, to pre-translational mechanisms. The lack of a strong correlation between
CYP2E1 mRNA and
protein suggests that this gene, like its rat orthologue, may be subject to pre-translational as well as translational and/or post-translational regulation.