Drugs online research references
J Biol Chem. 1996 Oct 25;271(43):27152-60.
Protein-DNA interactions at a drug-responsive element of the human apolipoprotein A-I gene.
Zhang X, Chen ZQ, Wang Z, Mohan W, Tam SP.
Department of Biochemistry, Queen's University, Kingston, Ontario K7L 3N6, Canada.
Previously, we demonstrated that when two human hepatoma cell lines, Hep3B and HepG2, were exposed to gemfibrozil, a hypolipidemic drug, a 2-fold induction in apolipoprotein A-I (apoA-I) mRNA levels resulted. To determine if mRNA stabilization was responsible for the changes in apoA-I mRNA levels, the half-lives for apoA-I mRNA were measured in the presence of actinomycin D with and without gemfibrozil. These experiments revealed no differences in stability. However, nuclear run-off assays indicated that the transcription rate of the apoA-I gene was increased 2-fold in gemfibrozil-treated cells. Transient transfection experiments also indicated that the induction of apoA-I mRNA level in response to gemfibrozil is mediated at the transcriptional level. We have identified two copies of the "drug-responsive element" (DRE) in the apoA-I promoter region that may be responsible for the increase in apoA-I transcriptional activity by gemfibrozil. Using gel mobility shift assays with a synthetic DRE oligonucleotide, we have demonstrated that exposure of Hep3B and HepG2 cells to gemfibrozil resulted in strong induction of a protein-DNA complex. The formation of this complex is highly sequence-specific as indicated by the DNA competition experiments. The drug-inducible nuclear proteins bind to the DRE of the human apoA-I gene with an apparent Kd of 4.1 nM. Methylation interference experiments have localized the contact sites of nuclear factors to the DRE region. Southwestern blot analyses have identified two groups of drug-inducible nuclear proteins with molecular masses of approximately 30 and 15 kDa. When a copy of synthetic DRE oligonucleotide was inserted upstream of the thymidine kinase promoter and luciferase reporter construct, a significant 2-fold induction in luciferase activity was observed in the presence of gemfibrozil following transient transfection of two human hepatoma cell lines, HepG2 and Hep3B. However, a plasmid containing one copy of mutated apoA-I-DRE oligomer did not confer responsiveness to gemfibrozil treatment. Furthermore, pGL2 (apoA-I -250 mutant DRE), which carried an internal mutation of the DRE in the human apoA-I proximal promoter region, showed no increase in luciferase activity in response to gemfibrozil. These results implicate protein-DNA interactions at the DRE region in the transcriptional induction of human apoA-I gene expression by gemfibrozil.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8900208&dopt=Abstract
Bioorg Med Chem. 1999 Feb;7(2):411-8.
Medium sized lactones with hypolipidaemic and antioxidant activity: synthesis and biological evaluation of promising dual-action anti-atherosclerosis drugs.
Baldazzi C, Calderoni F, Marotta E, Piani S, Righi P, Rosini G, Saguatti S, Tiozzo R, Calandra S, Venturelli F.
Dipartimento di Chimica Organica, A. Mangini, Universita di Bologna, Italy.
Macrocyclic lactones 1a-b have been synthesized and their potential therapeutic value evaluated. The key structural feature of these active 'chimera' compounds is the 12-membered lactone ring that brings together the well-known polysubstituted hydroquinone moiety of antioxidants and the alpha,alpha-dimethyl substituted acyl residue of gemfibrozil. Lactones 1a-b showed better activity than probucol, a classical phenolic antioxidant, in preventing the Cu++-induced oxidative modification of human LDL. The hypolipidaemic activity of the new lactones, evaluated as the inhibition of lipids biosynthesis in Hep-G2 cells, was comparable to that of gemfibrozil. These features, added to the lack of cytotoxicity, make this new class of medium sized lactones promising dual-action drugs useful as anti-atherosclerosis agents.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10218836&dopt=Abstract
Toxicol Sci. 1999 Mar;48(1):82-9.
The effect of peroxisome proliferators on mitochondrial bioenergetics.
Zhou S, Wallace KB.
Department of Biochemistry and Molecular Biology, University of Minnesota School of Medicine, Duluth 55812, USA.
Peroxisome proliferators are a group of structurally diverse chemicals that cause the proliferation of peroxisomes in rodents. The purpose of this investigation was to test the hypothesis that the shared effect of these compounds on peroxisome proliferation is mediated through a common inhibitory effect on mitochondrial bioenergetics. Freshly isolated rat liver mitochondria were energized with succinate. The effect of the chemicals on mitochondrial bioenergetics was analyzed by monitoring calcium-induced changes in membrane potential and swelling, as well as changes in mitochondrial respiration. Mitochondrial membrane potential was measured with a TPP(+)-sensitive electrode, and swelling was recorded spectrophotometrically. Mitochondrial oxygen uptake was monitored with a Clark-type oxygen electrode. Gemfibrozil and WY-14,643 induced the mitochondrial permeability transition as characterized by calcium-induced swelling and depolarization of membrane potential, both of which were inhibited by cyclosporine A. Fenofibrate, clofibrate, ciprofibrate and diethylhexyl phthalate, on the other hand, caused a direct dose-dependent depolarization of mitochondrial membrane potential. However, the mechanism of membrane depolarization varied among the test chemicals. Bezafibrate and trichloroethylene elicited no effect on succinate-supported mitochondrial bioenergetics. The results of this investigation demonstrate that although most, but not all, peroxisome proliferators interfere with mitochondrial bioenergetics, the specific biomolecular mechanism differs among the individual compounds.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10330687&dopt=Abstract
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