title: Differential effect of liver cirrhosis on the pregnane X receptor-mediated induction of CYP3A1 and 3A2 in the rat.
abstract: Conflicting results have been obtained by clinical studies investigating the effect of liver cirrhosis on enzyme induction. Because ethical concerns do not give consent for methodologically rigorous studies in humans, we addressed this question by examining the effect of the prototypical inducer dexamethasone (DEX) on the pregnane X receptor (PXR)-mediated induction of CYP3A1 and 3A2 in a validated animal model of liver cirrhosis obtained by exposure of rats to carbon tetrachloride. For this purpose, we assessed mRNA levels, protein expressions, and enzymatic activities of both CYP3A enzymes, as well as mRNA and protein expressions of PXR in rat populations rigorously stratified according to the severity of liver insufficiency. Constitutive mRNA and protein expressions of CYP3A1 and CYP3A2 and their basal enzyme activities were not affected by liver dysfunction. DEX treatment markedly increased steady-state mRNA level, protein content, and enzymatic activity of CYP3A1 in healthy and cirrhotic rats, irrespective of the degree of liver dysfunction. On the contrary, the inducing effect of DEX on gene and protein expressions and enzyme activity of CYP3A2 was preserved in moderate liver insufficiency, whereas it was greatly curtailed when liver insufficiency became severe. mRNA and protein expressions of PXR were neither reduced by liver dysfunction nor increased by DEX treatment. These results indicate that even the inducibility of cytochrome P450 isoforms under the transcriptional control of the same nuclear receptor may be differentially affected by cirrhosis and may partly explain why conflicting results were obtained by human studies.
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences (S.D.M., D.G., G.P., S.B., P.P.), Department of Molecular Medicine, Section of Anatomy (G.A., M.M.S.), and Department of Medicine, Surgical Pathology and Cytopathology Unit (C.M., L.A.), University of Padova, Padova, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: De Martin
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences (S.D.M., D.G., G.P., S.B., P.P.), Department of Molecular Medicine, Section of Anatomy (G.A., M.M.S.), and Department of Medicine, Surgical Pathology and Cytopathology Unit (C.M., L.A.), University of Padova, Padova, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Gabbia
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences (S.D.M., D.G., G.P., S.B., P.P.), Department of Molecular Medicine, Section of Anatomy (G.A., M.M.S.), and Department of Medicine, Surgical Pathology and Cytopathology Unit (C.M., L.A.), University of Padova, Padova, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Albertin
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences (S.D.M., D.G., G.P., S.B., P.P.), Department of Molecular Medicine, Section of Anatomy (G.A., M.M.S.), and Department of Medicine, Surgical Pathology and Cytopathology Unit (C.M., L.A.), University of Padova, Padova, Italy.
authors.forename: Maria Martina
authors.initials: MM
authors.lastname: Sfriso
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences (S.D.M., D.G., G.P., S.B., P.P.), Department of Molecular Medicine, Section of Anatomy (G.A., M.M.S.), and Department of Medicine, Surgical Pathology and Cytopathology Unit (C.M., L.A.), University of Padova, Padova, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Mescoli
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences (S.D.M., D.G., G.P., S.B., P.P.), Department of Molecular Medicine, Section of Anatomy (G.A., M.M.S.), and Department of Medicine, Surgical Pathology and Cytopathology Unit (C.M., L.A.), University of Padova, Padova, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Albertoni
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences (S.D.M., D.G., G.P., S.B., P.P.), Department of Molecular Medicine, Section of Anatomy (G.A., M.M.S.), and Department of Medicine, Surgical Pathology and Cytopathology Unit (C.M., L.A.), University of Padova, Padova, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Paliuri
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences (S.D.M., D.G., G.P., S.B., P.P.), Department of Molecular Medicine, Section of Anatomy (G.A., M.M.S.), and Department of Medicine, Surgical Pathology and Cytopathology Unit (C.M., L.A.), University of Padova, Padova, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Bova
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences (S.D.M., D.G., G.P., S.B., P.P.), Department of Molecular Medicine, Section of Anatomy (G.A., M.M.S.), and Department of Medicine, Surgical Pathology and Cytopathology Unit (C.M., L.A.), University of Padova, Padova, Italy pietro.palatini@unipd.it.
authors.forename: Pietro
authors.initials: P
authors.lastname: Palatini
mesh_terms: D000818:Animals; D002251:Carbon Tetrachloride; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D004790:Enzyme Induction; D015870:Gene Expression / Q000187:drug effects; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D000077297:Pregnane X Receptor; D051381:Rats; D011987:Receptors, Steroid / Q000096:biosynthesis* / Q000187:drug effects
chemical_list: D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D003907:Dexamethasone; D002251:Carbon Tetrachloride; C465260:Cyp3a2 protein, rat; C465138:Cyp3a23-3a1 protein, rat; D051544:Cytochrome P-450 CYP3A