Abstract
Although the induction of cytochrome P450 (CYP) has long been investigated in patients with cirrhosis, the question whether liver dysfunction impairs the response to CYP inducers still remains unresolved. Moreover, the mechanism underlying the possible effect of cirrhosis on induction has not been investigated. Since ethical constraints do not permit methodologically rigorous studies in humans, this question was addressed by investigating the effect of the prototypical inducer benzo[a]pyrene (BP) on CYP1A1 and CYP1A2 in cirrhotic rats stratified according to the severity of liver dysfunction. We simultaneously assessed mRNA level, protein expression and enzymatic activity of the CYP1A enzymes, as well as mRNA and protein expressions of the aryl hydrocarbon receptor (AhR), which mediates the BP effect. Basal mRNA and protein expressions of CYP1A1 were virtually absent in both healthy and cirrhotic rats. On the contrary, CYP1A2 mRNA, protein and enzyme activity were constitutively present in healthy rats and decreased significantly as liver function worsened. BP treatment markedly increased the concentrations of mRNA and immunodetectable protein, and the enzymatic activities of both CYP1A enzymes to similar levels in healthy and non-ascitic cirrhotic rats. Induced mRNA levels, protein expressions and enzymatic activities of both CYPs were much lower in ascitic rats and were proportionally reduced. Both constitutive and induced protein expressions of AhR were significantly lower in ascitic than in healthy rats. These results indicate that the inducibility of CYP1A enzymes is well preserved in compensated cirrhosis, whereas it is markedly reduced when liver dysfunction becomes severe. Induction appears to be impaired at the transcriptional level, due to the reduced expression of AhR, which controls the transcription of CYP1A genes.
Highlights
Drug interactions have became an important issue in health care, since they have often caused severe adverse effects leading to serious problems in both drug development and clinical practice [1]
This study has employed for the first time an animal population rigorously stratified according to the severity of liver cirrhosis to evaluate the effect of liver dysfunction on the inducibility of hepatic cytochrome P450 (CYP) enzymes
In agreement with literature data indicating that the constitutive expression of CYP1A1 is negligible in liver, while CYP1A2 is predominantly a hepatic enzyme [26,27,28], the qPCR determinations of this study show that CYP1A1 mRNA is virtually absent in the liver of uninduced rats, whereas CYP1A2 mRNA is present at a significant level in control healthy rats
Summary
Drug interactions have became an important issue in health care, since they have often caused severe adverse effects leading to serious problems in both drug development and clinical practice [1]. Since hepatic metabolism is the major pathway of elimination of most of the drugs on the market, and cytochromes P450 (CYPs) are the most common enzymes involved, most drug interactions arise from either inhibition or induction of CYP enzymes. Despite over 40 years of investigation, the effect of liver disease on the magnitude of drug interactions consequent upon enzyme induction is still an unresolved question, mainly because of the highly conflicting results obtained. Multiple factors may have contributed to the generation of conflicting results [8], a recent analysis of the literature [10] led us to conclude that these studies do not provide clear indications, mainly because they examined pathologically heterogeneous patient groups, with either unspecified degrees of liver dysfunction or including patients with mild and serious liver insufficiency
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