Isoform-Dependent Changes in Cytochrome P450-Mediated Drug Metabolism after Portal Vein Ligation in the Rat

Abstract

Background: Surgical removal of complicated liver tumors may be realized in two stages via selective portal vein ligation, inducing the atrophy of portally ligated lobes and the compensatory hypertrophy of nonligated liver lobes. Unlike morphological changes, functional aspects such as hepatic cytochrome P450 (CYP)-mediated drug metabolism remain vaguely understood, despite its critical role in both drug biotransformation and hepatic functional analysis. Our goal was the multilevel characterization of hepatic CYP-mediated drug metabolism after portal vein ligation in the rat. Methods: Male Wistar rats (n = 24, 210–230 g) were analyzed either untreated (controls; n = 4) or 24/48/72/168/336 h (n = 4 each) following portal vein ligation affecting approximately 80% of the liver parenchyma. Besides the weights of ligated and nonligated lobes, pentobarbital (30 mg/kg)-induced sleeping time, CYP1A(2), CYP 2B(1/2), CYP2C(6/11/13), CYP3A(1) enzyme activities, and corresponding isoform mRNA expressions, as well as CYP3A1 protein expression were determined by in vivo sleeping test, CYP isoform-selective assays, polymerase chain reaction, and immunohistochemistry, respectively. Results: Portal vein ligation triggered atrophy in ligated lobes and hypertrophy nonligated lobes. Sleeping time was transiently elevated (p = 0.0451). After an initial rise, CYP1A, CYP2B, and CYP3A enzyme activities dropped until 72 h, followed by a potent increase only in the nonligated lobes, paralleled by an early (24–48 h) transcriptional activation only in nonligated lobes. CYP2C enzyme activities and mRNA levels were bilaterally rapidly decreased, showing a late reconvergence only in nonligated lobes. CYP3A1 immunohistochemistry indicated substantial differences in positivity in the early period. Conclusions: Beyond the atrophy-hypertrophy complex, portal vein ligation generated a transient suppression of global and regional drug metabolism, re-established by an adaptive, CYP isoform-dependent transcriptional response of the nonligated lobes.

Quantifying Fat Zonation in Liver Lobules: An IntegratedMultiscale In-silico Model Combining DisturbedMicroperfusion and Fat Metabolism via aContinuum-Biomechanical Bi-scale, Tri-phasic Approach

“…Fat accumulation in hepatocytes, which leads to a partial obstruction of the hepatic sinusoids, is causing microperfusion impairment (Da Pereira et al, 2017). It is well known that changes in perfusion, such as hyperperfusion after liver resection or hypoperfusion in the case of portal vein embolism, will affect the metabolic capacity (Kovács et al, 2018;Takemura et al, 2006;Yao et al, 2011). It has also been shown, that hepatic steatosis itself, independent of the underlying perfusion disorder, may impact zonated metabolic function (Ashworth et al, 2016).…”

Quantifying fat zonation in liver lobules: an integrated multiscale in silico model combining disturbed microperfusion and fat metabolism via a continuum biomechanical bi-scale, tri-phasic approach

“…Fat accumulation in hepatocytes, which leads to a partial obstruction of the hepatic sinusoids, is causing microperfusion impairment (Da Pereira et al 2017 ). It is well known that changes in perfusion, such as hyperperfusion after liver resection or hypoperfusion in the case of portal vein embolism, will affect the metabolic capacity (Kovács et al 2018 ; Takemura et al 2006 ; Yao et al 2011 ). It has also been shown, that hepatic steatosis itself, independent of the underlying perfusion disorder, may impact zonated metabolic function (Ashworth et al 2016 ).…”