Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A newly synthesized taxoid originally from the Japanese yew Taxus cuspidata, 5-O-benzoylated taxinine K (BTK) was examined for its ability to reverse P-glycoprotein (P-gp) and multidrug resistance protein (MRP)-mediated multidrug resistance. BTK reversed the resistance to paclitaxel, doxorubicin (ADM), and vincristine (VCR) of KB-8-5 and KB-C2 cells that overexpress P-gp by directly interacting with P-gp. BTK also moderately reversed the resistance to ADM of KB/MRP cells that overexpress MRP. However, BTK neither inhibited the transporting activity of MRP nor reduced intracellular glutathione levels in KB/MRP cells. BTK shifted the distribution of ADM in KB/MRP cells from punctate cytoplasmic compartments to the nucleoplasm and cytoplasm by inhibiting acidification of cytoplasmic organelles. These two functions of BTK make it able to reverse both P-gp- and MRP-mediated MDR. BTK in combination with ADM should be useful for treating patients with tumors that overexpress both P-gp and MRP.
Mol Pharmacol 2000 Dec
PMID:Reversal of P-glycoprotein and multidrug-resistance protein-mediated drug resistance in KB cells by 5-O-benzoylated taxinine K. 1109 97

Subgroups of related short-chain dehydrogenase/reductase (SDR) family members serve as retinoid/androgen/estrogen metabolizing enzymes. These include retinol dehydrogenases (RoDHs) 1-3, cis-retinol/androgen dehydrogenase 1 and 2 (CRAD), retSDRs1-4, 9/11-cis-retinol dehydrogenase, and 17beta-hydroxysteroid dehydrogenase (17beta-HSD) types 6 and 9. Interaction with cellular retinol-binding protein (CRBP), the major physiological form of retinol, led to the identification and cDNA cloning of RoDH1. Probes for RoDH1 contributed to cDNA cloning many of the others. Some of these SDRs show specificity with all-trans-retinol (RoDH, retSDR, 17beta-HSD6 and 9) and others with 9 and/or 11-cis-retinol (CRAD, 9/11-cis-retinol dehydrogenase). Many have 3alpha-HSD activities with 3alpha-androstandiol as the most efficiently used substrate, followed by androsterone. In addition to 3alpha-HSD activity, CRAD2 shows relatively weak 17beta-HSD activity with testosterone. Rat 17beta-HSD6 and mouse 17beta-HSD9, which are not interspecies homologs, have efficient 17beta-HSD activities. 17beta-HSD6 has approximately 50% greater 17beta-HSD activity with estradiol than with 3alpha-androstandiol. With 3alpha-androstandiol, 17beta-HSD9 operates equally efficiently as a 17beta-HSD or a 3alpha-HSD. The multi-substrate nature of these SDRs allows for retinoid/steroid interactions. The ability of some these SDRs to access retinol bound with CRBP provides specificity in retinoid metabolism and allows retinoic acid biosynthesis and retinol esterification to continue, as CRBP protects retinol from the general cellular milieu.
Mol Cell Endocrinol 2001 Jan 22
PMID:17beta-Hydroxysteroid dehydrogenase type 9 and other short-chain dehydrogenases/reductases that catalyze retinoid, 17beta- and 3alpha-hydroxysteroid metabolism. 1116 18

17beta-Hydroxysteroid dehydrogenases (17beta-HSDs) regulate androgen and estrogen concentrations in mammals. By 1995, four distinct enzymes with 17beta-HSD activity had been identified--17beta-HSD-types 1 and 3, which, in vivo, are NADPH-dependent reductases; and 17beta-HSD-types 2 and 4, which, in vivo, are NAD(+)-dependent oxidases. Since then, six additional enzymes with 17beta-HSD activity have been isolated from mammals. With the exception of 17beta-HSD-type 5, which belongs to the aldoketo-reductase (AKR) family, these 17beta-HSDs belong to the short chain dehydrogenase/reductase (SDR) family. Several 17beta-HSDs appear to be examples of convergent evolution. That is, 17beta-HSD activity arose several times from different ancestors. Some 17beta-HSDs share a common ancestor with retinoid oxido-reductases and have retinol dehydrogenase activity. 17beta-HSD-types 2, 6 and 9 appear to have diverged from ancestral retinoid dehydrogenases early in the evolution of deuterostomes during the Cambrian, about 540 million years ago. This coincided with the origin of nuclear receptors for androgens and estrogens suggesting that expression of 17beta-HSDs had an important role in the early evolution of the physiological response to androgens and estrogens.
Mol Cell Endocrinol 2001 Jan 22
PMID:Evolution of 17beta-hydroxysteroid dehydrogenases and their role in androgen, estrogen and retinoid action. 1116 32

The developmental patterns of expression of beta-carotene cleavage enzyme activity were compared with those of retinal reductase and NAD-dependent retinol dehydrogenase activities in chick duodenum during the perinatal period. The beta-carotene cleavage enzyme activity was not detected in the duodenum before hatching, but it increased rapidly during 24 h after hatching. On the other hand, a considerable level of beta-carotene cleavage enzyme activity was observed in the liver of embryonic stages and its activity gradually rose during the perinatal period. Comparison of kinetic constants for the beta-carotene cleavage enzyme activities in the duodenum and the liver indicated that the enzyme in the duodenum possessed a lower affinity for beta-carotene than that in the liver. The retinal reductase activity was detected in the microsomes of the duodenum at the earliest time examined, i.e. day 16 of embryogenesis and its activity began to rise on the last day of embryogenesis, which was followed by a gradual increase until 1 day of age. The NAD-dependent retinol dehydrogenase activity was also seen in the microsomes of the duodenum in embryonic stages and its activity increased in parallel with the retinal reductase activity around the hatching period. These developmental inductions of beta-carotene cleavage enzyme and retinal reductase activities in the duodenum coincided with those of cellular retinol-binding protein, type II (CRBPII) and lecithin: retinol acyltransferase (LRAT). These results suggest that a co-ordinated induction mechanism should be operative for beta-carotene cleavage enzyme and retinal reductase, both of which are inevitable in the process of beta-carotene absorption and metabolism.
Comp Biochem Physiol B Biochem Mol Biol 2001 Mar
PMID:Co-ordinated induction of beta-carotene cleavage enzyme and retinal reductase in the duodenum of the developing chicks. 1125 May 37

The function of microbial MDRs remains a hotly debated subject. Given the very broad substrate specificities of some MDRs, like the RND pumps that can extrude all classes of amphipathic compounds (cationic, neutral, and anionic), it seems difficult to develop a rationale for pinpointing possible natural substrates of these translocases. At the same time, several clues can be used to guide our search for natural MDR substrates. One is the fact that amphipathic cations appear to be the preferred substrates of MDRs. These substances are extruded by MDRs of all 5 known families and are the almost exclusive substrates of SMR and MF family MDRs. The universal nature of amphipathic cations as MDR substrates suggests that these were the substances that fueled the evolution of MDR pumps. Two factors apparently favored this particular class of molecules for the role of original MDR substrates--need and opportunity. Unlike other substances, amphipathic cations accumulate in the cell driven by the membrane potential, which makes cations potentially the most dangerous toxins. At the same time, amphipathic cations are highly hydrated and do not permeate the membrane as readily as neutral compounds, making it feasible to design a defense based on an efflux pump. The paucity of known cationic (non-basic) antimicrobials might be a result of using MDR-expressing microbial cells for antibiotic discovery. Plant amphipathic cations, the berberine alkaloids, are good MDR substrates. The Berberis plants produce 5'-methoxyhydnocarpin-D, an MDR inhibitor that potentiates the action of berberine. It is suggested that the further evolution of MDR pumps was determined largely by the barrier function of the membrane they reside in. Thus Gram negative bacteria have an outer membrane barrier that slows the penetration of virtually all amphipathic molecules, and transenvelope MDRs of the RND and EmrAB-type extrude their substrates across this barrier. A low permeability of the cytoplasmic membrane of yeast similarly allows for the operation of broad-specificity ABC and MF MDRs. The presence of MDR sensors that regulate the expression of some MDR pumps strongly suggests that defense against external toxins is the function of these MDRs. The BmrR transcriptional activator of the MerR family induces expression of the Bmr pump in B. subtilis and is a sensor specifically designed to recognize amphipathic cations. Similarly, the OacR repressor binds chemically unrelated cations, which leads to the expression of the QacA pump in S. aureus. In E. coli, the EmrR sensor of the MarR repressor family binds unrelated neutral molecules, allowing for expression of the transenvelope EmrAB pump.
J Mol Microbiol Biotechnol 2001 Apr
PMID:In search of natural substrates and inhibitors of MDR pumps. 1132 80

In an endeavor to improve responsiveness of tumor cells to drug combination treatments, we analyzed the effect of 5-azacytidine (5AC) as a model compound for a new class of drugs, DNA-demethylating agents. We used parental K562/WT chronic myelogenous leukemia cells and a multidrug-resistant subline thereof, K562/ADM. Multidrug-resistant cells were more resistant to daunorubicin, but more sensitive to cisplatin than parental K562 cells as measured by growth inhibition and apoptosis assays. Resistance to daunorubicin can be explained by amplification of the MDR1 drug transporter gene. Cisplatin induced more DNA damage in specific genes and in the entire genome of K562/ADM cells compared to K562/WT cells using PCR stop assays and atomic absorption spectroscopy. Pretreatment with 5AC modulated the response of K562/ADM cells toward MDR-type drugs (daunorubicin, vincristine, etoposide) and reduced function and expression of MDR1 as analyzed by flow cytometry and RT-PCR. Analysis of CpG island methylation in the promotor region of the MDR1 gene by bisulfite sequencing and a methylation-sensitive HpaII-digestion/PCR approach revealed that methylation of the MDR1 promotor of K562/ADM cells was greater than in K562/WT cells. 5AC treatment completely abolished MDR1 promotor methylation. The unexpected observation that DNA demethylation by 5AC rather decreases than increases MDR1 expression in K5612/ADM cells points to still unexplored sequences in the MDR1 promotor whose transcriptional activity may be affected by the methylation status. 5AC pretreatment also modulated K562/WT and K562/ADM cells to non-MDR-type drugs such as cisplatin and increased cisplatin-induced DNA damage.
Blood Cells Mol Dis
PMID:5-Azacytidine modulates the response of sensitive and multidrug-resistant K562 leukemic cells to cytostatic drugs. 1148 78

Maleimide, N-ethyl-maleimide (NEM), and N-methyl-maleimide (NMM) were identified as potent catalytic inhibitors of purified human topoisomerase IIalpha, whereas the ring-saturated analog succinimide was completely inactive. Catalytic inhibition was not abrogated by topoisomerase II mutations that totally abolish the effect of bisdioxopiperazine compounds on catalytic inhibition, suggesting a different mode of action by these maleimides. Furthermore, in DNA cleavage assay maleimide and NEM could antagonize etoposide-induced DNA double-strand breaks. Consistently, maleimide could antagonize the effect of topoisomerase II poisons in three different in vivo assays: 1) In an alkaline elution assay maleimide protected against etoposide-induced DNA damage. 2) In a band depletion assay maleimide reduced etoposide-induced trapping of topoisomerase IIalpha and beta on DNA. 3) In a clonogenic assay maleimide antagonized the cytotoxicity of etoposide and daunorubicin on four different cell lines of human and murine origin. at-MDR cell lines with reduced nuclear topoisomerase IIalpha content are fully sensitive to maleimide, indicating that it is not a topoisomerase II poison in vivo. Our finding that topoisomerase II is sensitive to maleimide, NMM, and NEM but insensitive to succinimide demonstrates a strict requirement for the unsaturated ring bond for activity. We suggest that the observed antagonism in vitro and in vivo is caused by covalent modification of topoisomerase II cysteine residues reducing the amount of catalytically active enzyme sensitive to the action of topoisomerase II poisons.
Mol Pharmacol 2002 May
PMID:Maleimide is a potent inhibitor of topoisomerase II in vitro and in vivo: a new mode of catalytic inhibition. 1196 Nov 42

The multidrug resistance 1 (MDRI) gene and transcription factor 4(TCF4) gene are suggested to be involved in the WNT signalling pathway, the most important pathway altered in colorectal cancer. Mutations in both genes have been identified and associated with colorectal tumors exhibiting high microsatellite instability (MSI-H). In this study, we report on the distribution of functional polymorphisms in the MDR] gene and somatic frameshift mutations in the TCF4 gene coding mononucleotide repetition in 62 MSI-H colorectal tumors. Somatic frameshift mutations in(of) the TCF4 gene were identified in 24/62 (39%) of the studied MSI-H tumors. The estimated allele frequencies of functional polymorphisms in(of) exon 21 (2677 G>T, Ala893Ser) and exon 26(3435 C>T, Ilel 142I1e) of the MDR] gene were 0.42 and 0.46 in the controls and 0.54 (p=0.035) and 0.60 (p=0.017) in the MSI-H tumors. However, the allele frequency of both functional MDR] polymorphisms did not significantly differ between MSI-H tumors with TCF4 mutations and those without. These results support the involvement of the MDRI gene in the tumorgenesis of MSI-H tumors and also suggest that functional polymorphisms in the MDRI gene and mutations in the TCF4 gene are likely to occur independently in MSI-H tumors.
Cell Mol Biol Lett 2002
PMID:Functional MDR1 polymorphisms (G2677T and C3435T) and TCF4 mutations in colorectal tumors with high microsatellite instability. 1198 Apr 38

Screens were made for alcohol dehydrogenase (ADH) of the classical type (the MDR superfamily) in translations of human and other relevant genomes, corresponding to the organism types from which the enzyme was initially purified. Considerable multiplicities were detected in the dimeric enzymes from higher eukaryotes: seven forms in the human (plus three pseudogenes), all genes on chromosome 4, in the order class IV --> class Igamma --> class Ibeta --> class Ialpha --> class V --> class II --> class III, and eight forms in Arabidopsis thaliana (plus one pseudogene). These multiplicity patterns, and the species variability in the animal (human/mouse) and plant (Arabidopsis/pea) lines, suggest parallel but separate duplicatory events, giving rise to three families of dimeric MDR-ADH: class III, the animal non-class III, and the plant non-class III enzymes, with functions in formaldehyde elimination, in alcohol/aldehyde detoxication and in special pathways in higher eukaryotes. Multiplicity, although to a lesser extent, was also noted in tetrameric MDR-ADH, suggesting functional divergence between the dimeric and tetrameric enzymes. Combining these observations, at least five levels of divergence are reflected in the present ADH forms, corresponding to nodes at the SDR/MDR, the dimer/tetramer, the class III/non-class III, the class I/P, and the more recent class splits, each branch associated with separate functional patterns.
Cell Mol Life Sci 2002 Jun
PMID:Differential multiplicity of MDR alcohol dehydrogenases: enzyme genes in the human genome versus those in organisms initially studied. 1216 18

The biological functions of vitamin A in the epidermis are mediated by all-trans retinoic acid, which is biosynthesized from retinol in two oxidative reactions. The first step involves enzymatic conversion of retinol to retinaldehyde. The physiological significance and relative contributions of the various retinol dehydrogenases to the oxidation of retinol in epidermal cells remain unclear. We report the characterization of a retinol dehydrogenase/reductase of the SDR superfamily, hRoDH-E2, which is abundantly expressed in the epidermis, epidermal appendages and in cultured epidermal keratinocytes. Both in live keratinocytes and in isolated keratinocyte microsomes, where the enzyme normally localizes, hRoDH-E2 functions as a bona fide retinol dehydrogenase. In the prevailing oxidative reaction it recognizes both free- and CRBP-bound retinol, and shows preference toward NADP as a co-substrate. In comparison, hRoDH-E2 retinol dehydrogenase activity in the simple epithelial HEK 293 cells is much lower and in CHO cells is non-existent. hRoDH-E2 transcripts are distributed throughout the epidermal layers but are more abundant in the basal cells. In contrast, the protein is detected predominantly in the basal and the most differentiated living layers. Its synthesis is negatively regulated by retinoic acid. The biochemical properties and the differential expression of hRoDH-E2 in the strata where retinoic acid signaling is critical for epidermal homeostasis support a conclusion that hRoDH-E2 bears the characteristics of the major microsomal retinol dehydrogenase activity in the epidermal keratinocytes in physiological circumstances.
Mol Genet Metab 2003 Feb
PMID:Expression pattern and biochemical characteristics of a major epidermal retinol dehydrogenase. 1261 84


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>