当前位置： SCI文献检索 > BIOCHEMICAL PHARMACOLOGY期刊下所有文献 > Enzymology of the reductive bioactivation of SR 4233. A novel benzotriazine di-N-oxide hypoxic cell cytotoxin.

Enzymology of the reductive bioactivation of SR 4233. A novel benzotriazine di-N-oxide hypoxic cell cytotoxin.

Abstract：

:SR 4233 (3-amino-1,2,4-benzotriazine-1,4-dioxide) is a novel benzotriazine di-N-oxide which shows unusually high selective toxicity towards hypoxic cells, probably as a result of reductive bioactivation. Using an HPLC assay for the parent drug and its 2- and 4-electron reduction products (SR 4317 and SR 4330, respectively), we have examined the enzymology of SR 4233 reductive metabolism in vitro using a variety of different enzyme preparations. SR 4233 was converted extremely rapidly to SR 4317 under N2 by mouse liver microsomes, and showed a marked preference for NADPH over NADH as a reduced cofactor. The reaction was inhibited completely in air and boiled preparations. It was also inhibited by 78-86% in carbon monoxide (CO), implicating cytochrome P-450 as the major microsomal SR 4233 reductase. The kinetics of reductive metabolism of SR 4233 to SR 4317 by mouse liver microsomes conformed to Michaelis-Menten kinetics, with a Km of 1.4 mM and a Vmax of 950 nmol/min/mg protein. SR 4233 reduction was also catalysed by mouse liver cytosol under N2. However, rates were markedly slower than for microsomes and showed an equal dependency on NADH and NADPH. The cytosolic enzymes aldehyde oxidase and xanthine oxidase both catalysed SR 4233 reduction to SR 4317 under N2. Purified buttermilk xanthine oxidase also catalysed this reaction. In contrast to other enzyme preparations, DT-diaphorase from Walker 256 tumour cells reduced SR 4233 predominantly to SR 4330, and this reaction occurred under aerobic conditions. These data illustrate that SR 4233 is reduced rapidly by a wide variety of reductases. We propose that the therapeutic selectivity of SR 4233 will be controlled by the relative expression of reductases in tumour versus normal tissues, and in particular by the differential participation of putative activating versus detoxifying enzymes.

journal_name

Biochem Pharmacol

journal_title

Biochemical pharmacology

authors

Walton MI,Workman P

doi

10.1016/0006-2952(90)90119-6

subject

Has Abstract

pub_date

1990-06-01 00:00:00

pages

1735-42

issue

11

eissn

0006-2952

issn

1873-2968

pii

0006-2952(90)90119-6

journal_volume

39

pub_type

杂志文章

相关文献

BIOCHEMICAL PHARMACOLOGY文献大全
  • Use of mammalian DNA repair-deficient mutants to assess the effects of toxic metal compounds on DNA.

    abstract：:Wild-type and repair-deficient cell lines ( EM9 ) of Chinese Hamster Ovary cells were utilized to assess cytotoxic responses towards metals that produce lesions in DNA. Alkaline elution studies indicated that both CaCrO4 and HgCl2 induced single-strand breaks in the DNA. CaCrO4 and HgCl2 treatments of intact Chinese h...

    journal_title：Biochemical pharmacology

    pub_type： 杂志文章

    doi：10.1016/0006-2952(84)90289-2

    authors： Christie NT,Cantoni O,Evans RM,Meyn RE,Costa M

    更新日期：1984-05-15 00:00:00

  • Resistin facilitates VEGF-C-associated lymphangiogenesis by inhibiting miR-186 in human chondrosarcoma cells.

    abstract：:Chondrosarcoma is a common primary malignant tumor of the bone that can metastasize through the vascular system to other organs. A key step in the metastatic process, lymphangiogenesis, involves vascular endothelial growth factor-C (VEGF-C). However, the effects of lymphangiogenesis in chondrosarcoma metastasis remain...

    journal_title：Biochemical pharmacology

    pub_type： 杂志文章

    doi：10.1016/j.bcp.2018.05.001

    authors： Su CM,Tang CH,Chi MJ,Lin CY,Fong YC,Liu YC,Chen WC,Wang SW

    更新日期：2018-08-01 00:00:00

  • Correlation of a unique 220-kDa protein with vitamin D sensitivity in glioma cells.

    abstract：:We have investigated the antitumor and apoptotic effects of 1, 25-dihydroxyvitamin D(3) (VD(3)) in glioma cell lines and in primary cultures derived from surgical specimens from patients. Our results showed that certain glioma cells underwent apoptosis, whereas others were resistant. In an attempt to search for parame...

    journal_title：Biochemical pharmacology

    pub_type： 杂志文章

    doi：10.1016/s0006-2952(00)00438-x

    authors： Zou J,Landy H,Feun L,Xu R,Lampidis T,Wu CJ,Furst AJ,Savaraj N

    更新日期：2000-11-01 00:00:00

  • Evidence against involvement of calcium in carbon tetrachloride-dependent inhibition of lipid secretion by isolated hepatocytes.

    abstract：:Carbon tetrachloride (CCl4)-induced inhibition of very low density lipoprotein (VLDL) secretion was studied in isolated hepatocytes. The hypothesis that inhibition of secretion is due to altered calcium homeostasis following CCl4-dependent inhibition of endoplasmic reticulum calcium sequestration was investigated. Inh...

    journal_title：Biochemical pharmacology

    pub_type： 杂志文章

    doi：10.1016/0006-2952(84)90714-7

    authors： Pencil SD,Brattin WJ Jr,Glende EA Jr,Recknagel RO

    更新日期：1984-08-01 00:00:00

  • Leptin, gut, and food intake.

    abstract：:Hyperphagia (overeating) is often associated with energy over-storage and obesity, which may lead to a myriad of serious health problems, including heart disease, hypertension, and type 2 diabetes. Thus, understanding the complex pathological mechanisms underlying hyperphagia and obesity has an important clinical sign...

    journal_title：Biochemical pharmacology

    pub_type： 杂志文章,评审

    doi：10.1016/s0006-2952(02)00883-3

    authors： Attele AS,Shi ZQ,Yuan CS

    更新日期：2002-05-01 00:00:00

  • Site-directed mutagenesis at the human B2 receptor and molecular modelling to define the pharmacophore of non-peptide bradykinin receptor antagonists.

    abstract：:Combining site-directed mutagenesis with information obtained from molecular modelling of the bradykinin (BK) human B2 receptor (hB2R) as derived from the bovine rhodopsin crystal structure [Science 289 (2000) 739], we previously defined a putative binding mode for the non-peptide B2 receptor antagonists, FR173657 and...

    journal_title：Biochemical pharmacology

    pub_type： 杂志文章

    doi：10.1016/j.bcp.2003.09.034

    authors： Meini S,Cucchi P,Bellucci F,Catalani C,Faiella A,Rotondaro L,Quartara L,Giolitti A,Maggi CA

    更新日期：2004-02-15 00:00:00

  • Intestinal cell-specific vitamin D receptor (VDR)-mediated transcriptional regulation of CYP3A4 gene.

    abstract：:CYP3A4 is the most important drug-metabolizing enzyme that is involved in biotransformation of more than 50% of drugs. Pregnane X receptor (PXR) dominantly controls CYP3A4 inducibility in the liver, whereas vitamin D receptor (VDR) transactivates CYP3A4 in the intestine by secondary bile acids. Four major functional P...

    journal_title：Biochemical pharmacology

    pub_type： 杂志文章

    doi：10.1016/j.bcp.2009.08.017

    authors： Pavek P,Pospechova K,Svecova L,Syrova Z,Stejskalova L,Blazkova J,Dvorak Z,Blahos J

    更新日期：2010-01-15 00:00:00

  • Angiotensin metabolism by cerebral microvascular aminopeptidase A.

    abstract：:Porcine cerebral microvessels were isolated by differential sieving and centrifugation and were characterized by microscopic examination and marker enzyme enrichment (gamma-glutamyltransferase; EC 2.3.2.2). Purified microvessels contained a membrane-bound enzyme immunologically indistinguishable from renal aminopeptid...

    journal_title：Biochemical pharmacology

    pub_type： 杂志文章

    doi：10.1016/0006-2952(88)90712-5

    authors： Bausback HH,Churchill L,Ward PE

    更新日期：1988-01-15 00:00:00

  • Diversity of effects of two antitumor anthracycline analogs on the pathway of activation of PKC in intact human platelets.

    abstract：:Two antitumor antibiotics doxorubicin and daunorubicin were tested for their ability to influence the activation of protein kinase C in human platelets. Daunorubicin was found to inhibit the phosphorylation of the 40 K PKC substrate induced by thrombin and 12-O-tetradecanoyl-phorbol-13-acetate as well as the phosphory...

    journal_title：Biochemical pharmacology

    pub_type： 杂志文章

    doi：10.1016/0006-2952(88)90702-2

    authors： Lanzi C,Banfi P,Ravagnani F,Gambetta RA

    更新日期：1988-09-15 00:00:00

  • Impact of terminal dimethylation on the resistance profile of α-N-heterocyclic thiosemicarbazones.

    abstract：:Triapine is an α-N-heterocyclic thiosemicarbazone with promising anticancer activity against hematologic malignancies but widely ineffective against solid tumor types in clinical trials. The anticancer activity of thiosemicarbazones can be dramatically increased by terminal dimethylation. KP1089 is a gallium compound ...

    journal_title：Biochemical pharmacology

    pub_type： 杂志文章

    doi：10.1016/j.bcp.2012.03.004

    authors： Heffeter P,Pirker C,Kowol CR,Herrman G,Dornetshuber R,Miklos W,Jungwirth U,Koellensperger G,Keppler BK,Berger W

    更新日期：2012-06-15 00:00:00

  • Metabolism-dependent binding of the chlorinated insecticide DDT and its metabolite, DDD, to microsomal protein and lipids.

    abstract：:Dichlorodi[U-14C]phenyltrichloroethane ( [14C]DDT), incubated with rat hepatic microsomes and NADPH, produced reactive intermediates which covalently bound to microsomal protein and lipids. In atmospheric oxygen, DDT bound to microsomal protein; however, binding was increased up to approximately 70% by oxygen depletio...

    journal_title：Biochemical pharmacology

    pub_type： 杂志文章

    doi：10.1016/0006-2952(84)90483-0

    authors： Baker MT,Van Dyke RA

    更新日期：1984-01-15 00:00:00

  • Induction of G(1) cell cycle arrest and p27(KIP1) increase by panaxydol isolated from Panax ginseng.

    abstract：:Polyacetylenic compounds of Panax ginseng roots have been shown to inhibit growth of several human malignant tumor cell lines. Panaxydol is known to be one of the cytotoxic polyacetylenic compounds of P. ginseng. In this study, we first showed that panaxydol decreased markedly the proliferation, and to a lesser extent...

    journal_title：Biochemical pharmacology

    pub_type： 杂志文章

    doi：10.1016/s0006-2952(00)00235-5

    authors： Moon J,Yu SJ,Kim HS,Sohn J

    更新日期：2000-05-01 00:00:00

  • Effect of chronic phenobarbital treatment on folates and one-carbon enzymes in the rat.

    abstract：:Chronic oral phenobarbital treatment (50 mg/kg every 12 hr for 8 weeks), which was nontoxic and continuously protective against seizures in rats, significantly decreased folate concentration in liver (29%) but not in brain or plasma. The apparent activity of 5,10-methylenetetrahydrofolate reductase (MTR) in liver decr...

    journal_title：Biochemical pharmacology

    pub_type： 杂志文章

    doi：10.1016/0006-2952(84)90120-5

    authors： Carl GF,Smith DB

    更新日期：1984-11-01 00:00:00

  • Substituted flavones as aryl hydrocarbon (Ah) receptor agonists and antagonists.

    abstract：:The structure-dependent aryl hydrocarbon (Ah) receptor agonist and antagonist activities of the following substituted flavones were investigated: flavone, 4'-methoxy-, 4'-amino-, 4'-chloro-, 4'-bromo-, 4'-nitro-, 4'-chloro-3'-nitro-, 3'-amino-4'-hydroxy-, 3',4'-dichloro-, and 4'-iodoflavone. The halogenated flavones e...

    journal_title：Biochemical pharmacology

    pub_type： 杂志文章

    doi：10.1016/0006-2952(96)00063-9

    authors： Lu YF,Santostefano M,Cunningham BD,Threadgill MD,Safe S

    更新日期：1996-04-26 00:00:00

  • Transcriptional upregulation of gamma-globin by phenylbutyrate and analogous aromatic fatty acids.

    abstract：:Phenylbutyrate has been shown recently to induce fetal hemoglobin (HbF) production in patients with sickle cell anemia and beta thalassemia. We have now examined related aromatic fatty acids in order to define the range of active structures and identify plausible mechanisms of action. Structure-function analysis revea...

    journal_title：Biochemical pharmacology

    pub_type： 杂志文章

    doi：10.1016/0006-2952(96)00476-5

    authors： Hudgins WR,Fibach E,Safaya S,Rieder RF,Miller AC,Samid D

    更新日期：1996-10-25 00:00:00

  • Metabolism and RNA incorporation of cyclopentenyl cytosine in human colorectal cancer cells.

    abstract：:We studied the cytotoxicity and metabolism of the investigational cytidine analogue cyclopentenyl cytosine (CPE-C) in three human colorectal cancer cell lines: HCT 116, SNU-C4, and NCI-H630. CPE-C potently inhibited cell growth and decreased clonogenic capacity at concentrations achieved in murine and primate pharmaco...

    journal_title：Biochemical pharmacology

    pub_type： 杂志文章

    doi：10.1016/0006-2952(92)90218-8

    authors： Yee LK,Allegra CJ,Trepel JB,Grem JL

    更新日期：1992-04-01 00:00:00

  • Pharmacology of high-affinity binding of [3H](+/-)2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (ADTN) to bovine caudate nucleus tissue.

    abstract：:High-affinity binding of [3H](+/-)2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene [( 3H]-ADTN) was improved by use of a subcellular fraction (P4) of tissue obtained from calf brain. The highest concentration of binding sites was found in caudate nucleus which was evaluated extensively. Binding of 0.5 nM [3H]-ADTN ...

    journal_title：Biochemical pharmacology

    pub_type： 杂志文章

    doi：10.1016/0006-2952(83)90391-x

    authors： Arana GW,Baldessarini RJ,Lamont JS,Amlicke D,Neumeyer JL

    更新日期：1983-10-01 00:00:00

  • GABAA receptor-mediated neurotransmission: Not so simple after all.

    abstract：:GABAA receptors are ligand-gated ion channels that form a fundamental component of inhibitory neurotransmission in the central and peripheral nervous systems. However, since the initial recordings of inhibitory electrical activity of neurons in response to GABA, these receptors have been found to play a more complex r...

    journal_title：Biochemical pharmacology

    pub_type： 杂志文章

    doi：10.1016/j.bcp.2016.03.014

    authors： Knoflach F,Hernandez MC,Bertrand D

    更新日期：2016-09-01 00:00:00

  • Modulation by verapamil of vincristine pharmacokinetics and toxicity in mice bearing human tumor xenografts.

    abstract：:The effect of the calcium channel blocker verapamil (VRP) on the accumulation and retention of vincristine (VCR) has been examined in mice bearing xenografts of human rhabdomyosarcomas. The tumors were Rh18, moderately sensitive to VCR, and its subline, Rh18/VCR3, selected in vivo for primary resistance to VCR. Admini...

    journal_title：Biochemical pharmacology

    pub_type： 杂志文章

    doi：10.1016/0006-2952(89)90405-x

    authors： Horton JK,Thimmaiah KN,Houghton JA,Horowitz ME,Houghton PJ

    更新日期：1989-06-01 00:00:00

  • Interleukin-1beta converting enzyme (caspase-1) in intestinal inflammation.

    abstract：:An imbalance of T helper cell type 1 (Th1) versus type 2 (Th2) polarization in favor of Th1 cell subsets appears to be a key pathogenic mechanism in chronic inflammatory bowel disease (IBD), in particular in Crohn's disease. The interferon gamma-inducing factor interleukin (IL)-18 acts in strong synergism with the Th1...

    journal_title：Biochemical pharmacology

    pub_type： 杂志文章,评审

    doi：10.1016/s0006-2952(02)01064-x

    authors： Siegmund B

    更新日期：2002-07-01 00:00:00

  • Antiaggregatory activity in human platelets of potent antagonists of the P2Y 1 receptor.

    abstract：:Activation of the P2Y(1) nucleotide receptor in platelets by ADP causes changes in shape and aggregation, mediated by activation of phospholipase C (PLC). Recently, MRS2500(2-iodo-N(6)-methyl-(N)-methanocarba-2'-deoxyadenosine-3',5'-bisphosphate) was introduced as a highly potent and selective antagonist for this rece...

    journal_title：Biochemical pharmacology

    pub_type： 杂志文章

    doi：10.1016/j.bcp.2004.06.026

    authors： Cattaneo M,Lecchi A,Ohno M,Joshi BV,Besada P,Tchilibon S,Lombardi R,Bischofberger N,Harden TK,Jacobson KA

    更新日期：2004-11-15 00:00:00

  • Inhibition of interleukin-8 (CXCL8/IL-8) responses by repertaxin, a new inhibitor of the chemokine receptors CXCR1 and CXCR2.

    abstract：:Repertaxin is a new non-competitive allosteric blocker of interleukin-8 (CXCL8/IL-8) receptors (CXCR1/R2), which by locking CXCR1/R2 in an inactive conformation prevents receptor signaling and human polymorphonuclear leukocyte (PMN) chemotaxis. Given the unique mode of action of repertaxin it was important to examine ...

    journal_title：Biochemical pharmacology

    pub_type： 杂志文章

    doi：10.1016/j.bcp.2004.10.007

    authors： Casilli F,Bianchini A,Gloaguen I,Biordi L,Alesse E,Festuccia C,Cavalieri B,Strippoli R,Cervellera MN,Di Bitondo R,Ferretti E,Mainiero F,Bizzarri C,Colotta F,Bertini R

    更新日期：2005-02-01 00:00:00

  • Structure-guided creation of AcAP5-derived and platelet targeted factor Xa inhibitors.

    abstract：:Anticoagulants and anti-platelet agents are simultaneously administrated in clinical practice (i.e. percutaneous coronary intervention), which cause significant risk of systemic bleeding. Targeted delivery of anticoagulants to the activated platelets at sites of vascular injuries may condense the site-specific anticoa...

    journal_title：Biochemical pharmacology

    pub_type： 杂志文章

    doi：10.1016/j.bcp.2015.04.004

    authors： Zhu Y,Lin Y,Liu A,Shui M,Li R,Liu X,Hu W,Wang Y

    更新日期：2015-06-15 00:00:00

  • Actin cytoskeleton, tubular sodium and the renal synthesis of dopamine.

    abstract：:The present study has examined the effect of colchicine and cytochalasin B, two cytoskeleton disrupter compounds, on the formation of dopamine in slices of rat renal cortex loaded with exogenous L-3,4-dihydroxyphenylalanine (L-DOPA); the deamination of newly formed dopamine into 3,4-dihydroxyphenylacetic acid (DOPAC) ...

    journal_title：Biochemical pharmacology

    pub_type： 杂志文章

    doi：10.1016/0006-2952(92)90085-w

    authors： Soares-da-Silva P

    更新日期：1992-11-03 00:00:00

  • Novel modified adenosine 5'-triphosphate analogues pharmacologically characterized in human embryonic kidney 293 cells highly expressing rat brain P2Y(1) receptor: Biotinylated analogue potentially suitable for specific P2Y(1) receptor isolation.

    abstract：:Rat brain P2Y(1) (rP2Y(1)) receptor-transfected human embryonic kidney cells (HEK 293) were recently shown to have enhanced reactivity to both ATP and ADP (Vöhringer C, Schäfer R, Reiser G. Biochem Pharmacol 2000;59:791-800). Here, we demonstrated the usefulness of this cell line as a system for further studying novel...

    journal_title：Biochemical pharmacology

    pub_type： 杂志文章

    doi：10.1016/s0006-2952(01)00593-7

    authors： Zündorf G,Schäfer R,Vöhringer C,Halbfinger E,Fischer B,Reiser G

    更新日期：2001-05-15 00:00:00

  • Intracellular glutathione as a determinant of responsiveness to antitumor drugs.

    abstract：:The effect of glutathione depletion on cytotoxicity of the anthracycline daunorubicin, and of a copper:bis-thiosemicarbazone chelate, was examined in the P388 murine leukemia and its anthracycline-resistant subline, P388/ADR. Depletion of intracellular glutathione was accomplished through exposure to buthionine sulfox...

    journal_title：Biochemical pharmacology

    pub_type： 杂志文章

    doi：10.1016/0006-2952(86)90430-2

    authors： Romine MT,Kessel D

    更新日期：1986-10-01 00:00:00

  • Effects of perfluoro fatty acids on xenobiotic-metabolizing enzymes, enzymes which detoxify reactive forms of oxygen and lipid peroxidation in mouse liver.

    abstract：:Male mice were exposed via their diet to perfluoro fatty acids of various chain-lengths (2-10 carbon atoms) at different doses (0.02 and 0.1% weight) and for different periods of time (2-10 days). Thereafter, we monitored effects on liver and body weights and a number of hepatic parameters, including mitochondrial pro...

    journal_title：Biochemical pharmacology

    pub_type： 杂志文章

    doi：10.1016/0006-2952(92)90383-t

    authors： Permadi H,Lundgren B,Andersson K,DePierre JW

    更新日期：1992-09-25 00:00:00

  • Inhibition of glutathione peroxidase and glutathione transferase in mouse liver by misonidazole.

    abstract：:The mechanisms of toxicity and sensitization by the radiosensitizer misonidazole [1-(2-nitro-1-imidazolyl)-3-methoxy-2-propanol] are not well understood. We report here on the inhibition of total glutathione peroxidase (GSHPx), selenium-dependent glutathione peroxidase (selenium-GSHPx) and glutathione transferase (GSH...

    journal_title：Biochemical pharmacology

    pub_type： 杂志文章

    doi：10.1016/0006-2952(86)90399-0

    authors： Kumar KS,Weiss JF

    更新日期：1986-09-15 00:00:00

  • Targeting glial physiology and glutamate cycling in the treatment of depression.

    abstract：:Accumulating evidence indicates that dysfunction in amino acid neurotransmission contributes to the pathophysiology of depression. Consequently, the modulation of amino acid neurotransmission represents a new strategy for antidepressant development. While glutamate receptor ligands are known to have antidepressant eff...

    journal_title：Biochemical pharmacology

    pub_type： 杂志文章

    doi：10.1016/j.bcp.2009.04.008

    authors： Valentine GW,Sanacora G

    更新日期：2009-09-01 00:00:00

  • The peptidomimetic Lau-(Lys-βNSpe)6-NH2 antagonizes formyl peptide receptor 2 expressed in mouse neutrophils.

    abstract：:The formyl peptide receptor (FPR) gene family has a complex evolutionary history and comprises eight murine members but only three human representatives. To enable translation of results obtained in mouse models of human diseases, more comprehensive knowledge of the pharmacological similarities/differences between the...

    journal_title：Biochemical pharmacology

    pub_type： 杂志文章

    doi：10.1016/j.bcp.2016.09.004

    authors： Skovbakke SL,Winther M,Gabl M,Holdfeldt A,Linden S,Wang JM,Dahlgren C,Franzyk H,Forsman H

    更新日期：2016-11-01 00:00:00