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Interactions of the phenylpyrazolo steroid cortivazol with glucocorticoid receptors in steroid-sensitive and -resistant human leukemic cells. 1989

E B Thompson, and D Srivastava, and B H Johnson
Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston 77550.

The interactions of glucocorticoids with their receptors somehow determine the cellular responses seen. The high potency glucocorticoid cortivazol differs from the usual glucocorticoids in two ways, structurally and in binding to receptors. Cortivazol contains a phenylpyrazol fused at carbon atoms 2 and 3 to the A ring of the cyclophenathrene, replacing the supposedly essential 3-keto,4,5-double bond pattern of glucocorticoids. Cortivazol binds to the glucocorticoid receptor in the cytosol from CEM C7 cells (a human acute lymphoblastic leukemia line) in a fashion consistent with interaction with at least two sites. Standard glucocorticoids show only one-site binding. In mutant leukemia cells derived from CEM C7, resistant to kill by 10(-6) M dexamethasone and deficient in standard glucocorticoid binding sites, cortivazol still finds a binding site and kills the cells. In wild-type leukemia cells, the binding sites of cortivazol, those with both higher (Kd approximately 5 x 10(-10) M) and lower (Kd approximately 1 x 10(-8] affinity appear to be on forms of the glucocorticoid receptor itself, and not on two different classes of molecules.

UI MeSH Term Description Entries
D008961 Models, Structural A representation, generally small in scale, to show the structure, construction, or appearance of something. (From Random House Unabridged Dictionary, 2d ed) Model, Structural,Structural Model,Structural Models
D009154 Mutation Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations. Mutations
D011281 Pregnatrienes Pregnane derivatives containing three double bonds in the ring structures.
D011965 Receptors, Glucocorticoid Cytoplasmic proteins that specifically bind glucocorticoids and mediate their cellular effects. The glucocorticoid receptor-glucocorticoid complex acts in the nucleus to induce transcription of DNA. Glucocorticoids were named for their actions on blood glucose concentration, but they have equally important effects on protein and fat metabolism. Cortisol is the most important example. Corticoid Type II Receptor,Glucocorticoid Receptors,Glucocorticoids Receptor,Corticoid II Receptor,Corticoid Type II Receptors,Glucocorticoid Receptor,Receptors, Corticoid II,Receptors, Corticoid Type II,Receptors, Glucocorticoids,Corticoid II Receptors,Glucocorticoids Receptors,Receptor, Corticoid II,Receptor, Glucocorticoid,Receptor, Glucocorticoids
D003907 Dexamethasone An anti-inflammatory 9-fluoro-glucocorticoid. Hexadecadrol,Decaject,Decaject-L.A.,Decameth,Decaspray,Dexasone,Dexpak,Hexadrol,Maxidex,Methylfluorprednisolone,Millicorten,Oradexon,Decaject L.A.
D004351 Drug Resistance Diminished or failed response of an organism, disease or tissue to the intended effectiveness of a chemical or drug. It should be differentiated from DRUG TOLERANCE which is the progressive diminution of the susceptibility of a human or animal to the effects of a drug, as a result of continued administration. Resistance, Drug
D004963 Estrenes Unsaturated derivatives of the ESTRANES with methyl groups at carbon-13, with no carbon at carbon-10, and with no more than one carbon at carbon-17. They must contain one or more double bonds. 19-Norandrostenes,19 Norandrostenes
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000483 Alleles Variant forms of the same gene, occupying the same locus on homologous CHROMOSOMES, and governing the variants in production of the same gene product. Allelomorphs,Allele,Allelomorph
D001665 Binding Sites The parts of a macromolecule that directly participate in its specific combination with another molecule. Combining Site,Binding Site,Combining Sites,Site, Binding,Site, Combining,Sites, Binding,Sites, Combining

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