Our studies were conducted to explore the role of hepatic fatty acid-binding protein (L-FABP) in fatty acid transport to the nucleus. Purified rat L-FABP facilitated the specific interaction of [(3)H]oleic acid with the nuclei. L-FABP complexed with unlabeled oleic acid decreased the nuclear association of [(3)H]oleic acid:L-FABP; however, oleic acid-saturated bovine serum albumin (BSA) or fatty acid-free L-FABP did not. The peroxisome-proliferating agents LY171883, bezafibrate, and WY-14,643 were also effective competitors when complexed to L-FABP. Nuclease treatment did not affect the nuclear association of [(3)H]oleic acid:L-FABP; however, proteinase treatment of the nuclei abolished the binding. Nuclei incubated with fluorescein-conjugated L-FABP in the presence of oleic acid were highly fluorescent whereas no fluorescence was observed in reactions lacking oleic acid, suggesting that L-FABP itself was binding to the nuclei. The nuclear binding of FABP was concentration dependent, saturable, and competitive. LY189585, a ligand for L-FABP, also facilitated the nuclear binding of fluorescein-conjugated L-FABP, although it was less potent than oleic acid. A structural analog that does not bind L-FABP, LY163443, was relatively inactive in stimulating the nuclear binding. Potential interactions between L-FABP and nuclear proteins were analyzed by Far-Western blotting and identified a 33-kDa protein in the 500 mm NaCl extract of rat hepatocyte nuclei that bound strongly to biotinylated L-FABP. Oleic acid enhanced the interaction of L-FABP with the 33-kDa protein as well as other nuclear proteins. We propose that L-FABP is involved in communicating the state of fatty acid metabolism from the cytosol to the nucleus through an interaction with lipid mediators that are involved in nuclear signal transduction.

21 Apr 1997·European journal of medical research

Effects of progesterone and leukotriene receptor antagonists in experimental models of P-glycoprotein-related resistance.

Article

Author: Pelka-Fleischer, R ; Wilmanns, W ; Denzlinger, C ; Nuessler, V ; Zwierzina, H

P-glycoprotein (P-gp)-related resistance is one of the most intensively investigated mechanisms of multidrug resistance, but the search for better modulators and better modulator combinations has just begun. The present work was performed to determine whether leukotriene LTD4 /LTE4 receptor antagonists such as FPL-55712, Ly-163443, Ly-171883, MK-571 and the progesterone receptor antagonist RU-38486 are potential P-gp modulators in models of P-gp-related resistance. Additionally, the P-gp modulating potency of the combination of RU-38486 and verapamil was investigated. P-gp expression was determined with the monoclonal antibody 4E3.16, and functional activity was assessed by the Rhodamine123 (R123) accumulation assay. Efficacy of the modulators was determined with the MTT test and the R123 accumulation assay. The in vitro examinations were done in the P-gp-resistant human T-lymphoblastic cell lines CCRF-CEM/ ACT400 and CCRF-CEM/VCR1000. No P-gp-modulating effect was observed with Ly-163443, Ly-171883, FPL-55712 or MK-571. A significant (p<0.05) cytotoxicity of the examined modulators per se (without actinomycin D or vincristine) was demonstrated only for verapamil at a concentration of 10 microM. At a concentration of 10 microM a significant (p<0.05) P-gp modulating effect was observed with RU-38486, which was even more pronounced than the effect of verapamil as determined by the MTT test. Using the R123 accumulation assay it was shown that the combination of RU-38486 (6 microM and 10 microM) and verapamil additively increased (p<0.05) the percentage of accumulating cells. This additive effect was reflected by a significantly (p<0.05) enhanced efficacy of the combination of drugs with respect to inhibition of cell proliferation. The data presented advocate testing of new potential P-gp modulator combinations, such as RU-38486 and verapamil, with the aim of increasing efficacy and simultaneously reducing side effects.

01 Mar 1996·Toxicology and Applied PharmacologyQ3 · MEDICINE

The Effects of Peroxisome Proliferators on Protein Abundances in Mouse Liver

Q3 · MEDICINE

Article

Author: Anderson Nl ; Foxworthy P ; Eacho P ; Richardson F ; Esquer-Blasco R

We have investigated the effects of five peroxisome proliferators (PPs : clofibric acid, DEHP, WY14,643, nafenopin, and LY171883) on the abundances of a large number of proteins in the livers of treated mice at 5- and 35-day time points. LY171883 was investigated at a range of doses, and one of its close structural analogs that is not a peroxisome proliferator (LY163443) was included as a negative control compound. Liver samples were analyzed by quantitative 2-D electrophoresis. Data for a selected set of 107 liver protein spots that respond strongly to at least one of the test compounds was subjected to principal component analysis to search for global protein pattern changes. The first component (PC1) accounted for 51% of the total data variance and was identified as a global measure of peroxisome proliferation by its correlation with enzymatic peroxisomal beta-oxidation. Component PC2 (7%) separated 5- and 35-day exposures, and PC3 (5%) separated groups treated with LY163443 from the rest. We used PC1 as a surrogate for equivalent dose in order to examine the effects of diverse compounds, with widely differing potencies, on a common scale. Analyzed in this way, the data indicate that all the peroxisome proliferators tested produce effects over wide time and dose ranges that fall on or near a single curve. Examination of specific protein responses showed that many proteins individually show a unified response curve, but that curves for different proteins were different. In particular, it appears that some constitutive proteins showing modest inductions with a high dose plateau (such as cytosolic epoxide hydrolase) are inducible at lower doses than some proteins showing very strong, nonplateaued inductions (such as the 80-kDa peroxisomal bifunctional enzyme). The results provide support for a unified receptor-based mechanism controlling the main PP response, but demonstrate that individual responsive genes can show quite different dose-response curves.

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Indication	Highest Phase	Country/Location	Organization	Date
Asthma	Preclinical	US	Eli Lilly & Co.	01 May 1986

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