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 steadystate 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.

UDP‐Glucuronosyltransferase (UGT)‐mediated attenuations of cytochrome P450 3A4 activity: UGT isoform‐dependent mechanism of suppression

“…For further evaluation of the role of CYP3A–UGT1A interactions, we focused on dexamethasone, a strong inducer of hepatic CYP3A1, CYP3A2, UGT1A1, and 1A6 in rat (De Martin et al, ; Ghosal, Sadrieh, Reik, Levin, & Thomas, ; Jemnitz, Veres, Monostory, & Vereczkey, ). The UGT‐mediated suppression of CYP3As should be affected if dexamethasone treatment induces CYP3As and UGT1As to different extents.…”

Fucus vesiculosus and Ascophyllum nodosum Ameliorate Liver Function by Reducing Diet-Induced Steatosis in Rats

“…Ten male Wistar rats, aged 5 weeks (body weight 150-170 g), were obtained from Charles River Italia (Calco, Lecco, Italy). They were kept under controlled environmental conditions and fed with standard diet for 2 weeks before the beginning of the treatment [31]. Then, the animals were randomized into two experimental groups, both fed with high-fat diet (HFD = kcal from 23.5% protein, 18.4% carbohydrate, and 60.3% fat; Altromin; Lage, Germany).…”

Xyloketal B, a marine compound, acts on a network of molecular proteins and regulates the activity and expression of rat cytochrome P450 3a: a bioinformatic and animal study

“…For example, microRNAs are the major determinants of gene expression at the post-transcriptional level, suppressing gene expression by mRNA cleavage or translational inhibition. 53 , 54 Moreover, it has been reported that the expression of rat hepatic Cyp3a2 is predisposed to regulation by nuclear transcription factors or nuclear receptors, 55 – 57 which may also be involved in the regulatory effect of XKB on expression of rat Cyp3a2.…”