Association of Liver Stiffness with Hepatic Expression of Pharmacokinetically Important Genes in Alcoholic Liver Disease

Theile, Dirk; Haefeli, Walter E.; Seitz, Helmut K.; Millonig, Gunda; Weiß, Johanna; Mueller, Sebastian

doi:10.1111/j.1530-0277.2012.01901.x

Cited by 17 publications

(18 citation statements)

References 49 publications

(53 reference statements)

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“…This is in contrast to the previous pilot study that showed significant differences between KS of allografts with stable and impaired function but did not define and use criteria for reliable measurements [17]. It also clearly contrasts recent data obtained in liver where stiffness correlates well with liver function [30].…”

Section: Discussioncontrasting

confidence: 55%

Assessment of renal allograft fibrosis by transient elastography

et al. 2013

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SummaryTransient elastography (TE, Fibroscan) has been established as a noninvasive assessment tool of liver fibrosis. We evaluated potentials and limitations of TE for identifying renal allograft fibrosis. The technical possibility of kidney examination by TE was assessed in two 10-week-old German landrace pigs and kidney stiffness (KS) was evaluated in 164 renal transplant patients. KS could be determined in all animals at the pole and pars media (29 AE 10 kPa vs. 31 AE 17 kPa). In human renal allografts KS was successfully performed in 94.5% of the test series with reliable results in 72% of the measurements. Mean KS at the pole or pars media were comparable (35.0 AE 19.9 kPa vs. 33.2 AE 18.6 kPa). Significantly higher KS was detected in renal allografts with histologically confirmed advanced fibrosis. Bodymass-index, skin-allograft distance, and peri or intrarenal fluid accumulation were important confounders of successful KS measurements (BMI: r = À0.31; P < 0.001; distance: r = À0.50; P < 0.001). Notably, KS did not correlate with renal function. TE represents a noninvasive approach in selected transplant recipients to identify allografts with severe fibrosis. The heterogeneous kidney morphology and several other confounding factors negatively affect measurability of KS by TE. Further technical modifications are required to improve applicability of TE for kidney assessment.

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Section: Discussioncontrasting

confidence: 55%

Assessment of renal allograft fibrosis by transient elastography

et al. 2013

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“…), which may interfere with CYP expression and hepatic drug metabolism. Supporting this, the Heidelberg workgroup found reduced CYP2E1 expression in liver fibrosis, identified with liver stiffness elastography, as well as boosted CYP expression, drug metabolism, and subsequently increased, carcinogenic etheno-DNA adducts in (nonfibrotic) alcoholic liver disease [41, 42]. Therefore, the in-depth evaluation of CYP regulation in liver disease states is also of chief clinical relevance.…”

Section: Discussionmentioning

confidence: 94%

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

et al. 2018

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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.

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“…Alternatively, the observed increases of protein expression in this particular experimental setting might simply be too small to cause detectable activity changes in the flow cytometry approach. Irrespective of these uncertainties, drug transporters shall still have an impact on pharmacokinetics in alcoholics because other important drug transporters beside Pgp were also influenced (Figure ) and were reported to be slightly differentially expressed in alcoholics compared with healthy controls . The net functional consequences of these manifold slight upregulations of drug transporters are admittedly difficult to estimate, but clinical trials determining pharmacokinetics of selective Pgp substrates such as digoxin can clarify whether Pgp changes truly affect drug kinetics in chronic alcoholics.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, we have recently demonstrated that chronic alcoholics without pathologically increased liver stiffness (i.e. with absence of severe alcoholic liver disease) tend to exhibit higher hepatic messenger RNA (mRNA) expression of pharmacokinetically important genes compared with healthy controls . With respect to drug transporters, no definite data exist whether ethanol alters expression and activity of human drug transporters at pharmacological barriers such as the intestine despite convincing data from experiments with ethanol‐treated rats exhibiting increased intestinal efflux transporter expression and activity upon alcohol exposure …”

Section: Introductionmentioning

confidence: 99%

“…with absence of severe alcoholic liver disease) tend to exhibit higher hepatic messenger RNA (mRNA) expression of pharmacokinetically important genes compared with healthy controls. [14] With respect to drug transporters, no definite data exist whether ethanol alters expression and activity of human drug transporters at pharmacological barriers such as the intestine despite convincing data from experiments with ethanol-treated rats exhibiting increased intestinal efflux transporter expression and activity upon alcohol exposure. [15,16] This study aimed at comprehensively investigating the complex interaction between alcohol exposure and relevant genes of drug disposition with a special emphasis on drug transporters.…”

Section: Introductionmentioning

confidence: 99%

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