Little is known about the impact of morphological disorders in distinct zones on metabolic zonation. It was described recently that periportal fibrosis did affect the expression of CYP proteins, a set of pericentrally located drug-metabolizing enzymes. Here, we investigated whether periportal steatosis might have a similar effect. Periportal steatosis was induced in C57BL6/J mice by feeding a high-fat diet with low methionine/choline content for either two or four weeks. Steatosis severity was quantified using image analysis. Triglycerides and CYP activity were quantified in photometric or fluorometric assay. The distribution of CYP3A4, CYP1A2, CYP2D6, and CYP2E1 was visualized by immunohistochemistry. Pharmacokinetic parameters of test drugs were determined after injecting a drug cocktail (caffeine, codeine, and midazolam). The dietary model resulted in moderate to severe mixed steatosis confined to periportal and midzonal areas. Periportal steatosis did not affect the zonal distribution of CYP expression but the activity of selected CYPs was associated with steatosis severity. Caffeine elimination was accelerated by microvesicular steatosis, whereas midazolam elimination was delayed in macrovesicular steatosis. In summary, periportal steatosis affected parameters of pericentrally located drug metabolism. This observation calls for further investigations of the highly complex interrelationship between steatosis and drug metabolism and underlying signaling mechanisms.

A 60-membered library of vitamin A-functionalized P(MMA-stat-DMAEMA)-b-PPEGMA block copolymers was synthesized by RAFT polymerization. From these, nanoparticles containing genetic material were formulated and fully characterized.

<p>A 60-membered library of vitamin A-functionalized P(MMA-<i>stat</i>-DMAEMA)-<i>b</i>-PPEGMA block copolymers was synthesized by RAFT polymerization. Subsequently, retinoic acid was coupled to hydroxyl groups present in the hydrophilic PPEGMA block. The polymers were investigated for their ability to encapsulate ribonucleic acids through nanoparticle (NP) formulation using the emulsion/solvent evaporation method. The localization of vitamin A in surface-near regions of the NPs was indicated by surface enhanced Raman spectroscopy, and the interaction of the NPs with a retinol binding protein was investigated by analytical ultracentrifugation. The systematic analysis of the NP library in terms of the encapsulation efficiency of the ribonucleic acids, the toxicity of the NPs, and the cellular uptake helped identifying suitable candidates for cellular internalization studies. The cell uptake was investigated by flow cytometry and fluorescence microscopy and reveals structure dependent uptake behavior of the examined particles. </p>

<p>A 60-membered library of vitamin A-functionalized P(MMA-<i>stat</i>-DMAEMA)-<i>b</i>-PPEGMA block copolymers was synthesized by RAFT polymerization. Subsequently, retinoic acid was coupled to hydroxyl groups present in the hydrophilic PPEGMA block. The polymers were investigated for their ability to encapsulate ribonucleic acids through nanoparticle (NP) formulation using the emulsion/solvent evaporation method. The localization of vitamin A in surface-near regions of the NPs was indicated by surface enhanced Raman spectroscopy, and the interaction of the NPs with a retinol binding protein was investigated by analytical ultracentrifugation. The systematic analysis of the NP library in terms of the encapsulation efficiency of the ribonucleic acids, the toxicity of the NPs, and the cellular uptake helped identifying suitable candidates for cellular internalization studies. The cell uptake was investigated by flow cytometry and fluorescence microscopy and reveals structure dependent uptake behavior of the examined particles. </p>