title: Severe liver cirrhosis markedly reduces AhR-mediated induction of cytochrome P450 in rats by decreasing the transcription of target genes.
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.
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy.
authors.forename: Maura
authors.initials: M
authors.lastname: Floreani
authors.forename: Sara
authors.initials: S
authors.lastname: De Martin
authors.forename: Daniela
authors.initials: D
authors.lastname: Gabbia
authors.forename: Massimo
authors.initials: M
authors.lastname: Barbierato
authors.forename: Alberto
authors.initials: A
authors.lastname: Nassi
authors.forename: Claudia
authors.initials: C
authors.lastname: Mescoli
authors.forename: Rocco
authors.initials: R
authors.lastname: Orlando
authors.forename: Sergio
authors.initials: S
authors.lastname: Bova
authors.forename: Paolo
authors.initials: P
authors.lastname: Angeli
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Gola
authors.forename: Antonietta
authors.initials: A
authors.lastname: Sticca
authors.forename: Pietro
authors.initials: P
authors.lastname: Palatini
mesh_terms: D000818:Animals; D001201:Ascites / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D001564:Benzo(a)pyrene; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism*; D019388:Cytochrome P-450 CYP1A2; D003580:Cytochromes / Q000235:genetics / Q000378:metabolism*; D004790:Enzyme Induction / Q000235:genetics*; D005786:Gene Expression Regulation; D008099:Liver / Q000201:enzymology* / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008111:Liver Function Tests; D008297:Male; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D012720:Severity of Illness Index; D014158:Transcription, Genetic
chemical_list: D003580:Cytochromes; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D001564:Benzo(a)pyrene; C017170:Cyp1a2 protein, rat; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2