Published online Nov 14, 2017. doi: 10.3748/wjg.v23.i42.7519
Peer-review started: August 7, 2017
First decision: August 30, 2017
Revised: September 18, 2017
Accepted: October 17, 2017
Article in press: October 17, 2017
Published online: November 14, 2017
To ascertain whether cholestasis affects the expression of two CYP3A isoforms (CYP3A1 and CYP3A2) and of pregnane X receptor (PXR) and constitutive androstane receptor (CAR).
Cholestasis was induced by bile duct ligation in 16 male Wistar rats; whereas 8 sham-operated rats were used as controls. Severity of cholestasis was assessed on histological examination of liver sections, and serum concentrations of albumin, AST, ALT, GGT, ALPK and bilirubin. Gene and protein expressions of PXR, CAR, CYP3A1 and CYP3A2 were assessed by means of qRT-PCR and Western blot, respectively. Alterations in CYP3A activity were measured by calculating the kinetic parameters of 4-OH and 1’-OH-midazolam hydroxylation, marker reactions for CYP3A enzymes.
The mRNA and protein expression of CYP3A1 increased significantly in mild cholestasis (P < 0.01). At variance, mRNA and protein expression of CYP3A2 didn’t change in mild cholestasis, whereas the expression and activity of both CYP3A1 and CYP3A2 decreased dramatically when cholestasis became severe. Consistently with these observations, the nuclear expression of both PXR and CAR, which was measured because they both translocate into the cell nucleus after their activation, virtually disappeared in the late stage of cholestatic injury, after an initial increase. These results indicate that early- and late-stage cholestasis affects CYP3A-mediated drug metabolism differently, probably as consequence of the different activation of PXR and CAR.
Early- and late-stage cholestasis affects CYP3A-mediated drug metabolism differently. PXR and CAR might be targeted therapeutically to promote CYP3A-mediated liver detoxification.
Core tip: We demonstrated that early- and late-stage cholestasis affects CYP3A-mediated metabolism differently, probably as consequence of the different activation of pregnane X receptor (PXR) and constitutive androstane receptor (CAR). As a consequence, cholestatic patients may have an altered drug metabolism: in the early stage due to the induction of CYP3A enzymes; and in the late stage due to the high deposition of fibrotic liver and consequent hepatocyte loss. Secondly, since PXR activation is known to induce alternative hepatic export routes and detoxification enzymes, the induction of these cellular pathways with PXR and/or CAR agonists could be exploited as a therapeutic strategy for the management of cholestatic diseases.