scholarly journals Drug-induced conversion of liver haem into modified porphyrins. Evidence for two classes of products

1980 ◽  
Vol 187 (1) ◽  
pp. 285-288 ◽  
Author(s):  
F De Matteis ◽  
A H Gibbs
Keyword(s):  
Inhibitory Activity ◽  
Spectral Properties ◽  
Drug Induced ◽  
Mechanism Of Inhibition ◽  
Green Pigments

A porphyrin with inhibitory activity towards protohaem ferro-lyase (EC 4.99.1.1) was isolated from the liver of mice given either griseofulvin or isogriseofulvin. This porphyrin resembles closely in chromatographic and spectral properties the inhibitory pigment isolated after treatment with 3,5-diethoxycarbonyl-1,4-dihydrocollidine, but differs from other green pigments that do not inhibit protohaem ferro-lyase. A hypothesis is proposed to account for the differences in properties between the two groups of pigments and for the mechanism of inhibition of the enzyme.

Mechanism of inhibition of succinate oxidase by products of oxidation of o-dihydroxycoumarins

1980 ◽  
Vol 45 (2) ◽  
pp. 641-652
Author(s):  
Petr Zbořil
Keyword(s):  
Inhibitory Activity ◽  
Oxidase Activity ◽  
Enzyme Preparation ◽  
Inhibitory Effects ◽  
Anaerobic Conditions ◽  
Long Period ◽  
Mechanism Of Inhibition ◽  
Intermediary Product ◽  
Succinate Oxidase ◽  
By Products

Semiquinone is an intermediary product of the oxidation of daphnetin (7,8-dihydroxycoumarin) and esculetin (6,7-dihydroxycoumarin) by diphenol oxidase; its concentration rapidly decreases. When the oxidation is effected by ferricytochrome c, the concentration of the semiquinone remains practically constant for a long period. Similarly, the ability of the products of daphnetin oxidation by diphenol oxidase to inhibit succinate oxidase activity in mitochondrial fragments rapidly decreases with time; the decrease is considerably slower in the case of cytochrome c. The inhibitory activity of the product decreases with time also during esculetin oxidation by ferricyanide. This indicates that the inhibitory effects must be ascribed predominantly to the semiquinone, the quinone is less efficient. The inhibition of succinate oxidase or succinate dehydrogenase was strongly decreased when the enzyme preparation of Keilin and Hartree was incubated with esculetin and ferricyanide in the presence of KCN or under anaerobic conditions. This demonstrates that the reaction of the inhibitor with the enzyme either involves subsequent oxidations or that the inhibitor preferentially reacts with the oxidized form of the sensitive component of the respiratory chain. The second alternative is very little probable since there is no correlation between the degree of inhibition and the binding of the inhibitor to mitochondrial fragments.

The Inhibitory Activity of Plants from Central Argentina on p-Hydroxyphenylpyruvate Dioxygenase. Isolation and Mechanism of Inhibition of a Flavanone from Flourensia oolepis

Planta Medica ◽  
2015 ◽  
Vol 81 (15) ◽  
pp. 1382-1391 ◽  
Author(s):  
María Chiari ◽  
Leonardo Tosoni ◽  
Mariana Joray ◽  
Georgina Diaz Napal ◽  
Sara Palacios ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Central Argentina ◽  
Mechanism Of Inhibition

scholarly journals Drug-induced agranulocytosis: in vitro evidence for immune suppression of granulopoiesis and a cross-reacting lymphocyte antibody

Blood ◽  
1979 ◽  
Vol 54 (2) ◽  
pp. 501-512 ◽  
Author(s):  
R Taetle ◽  
TA Lane ◽  
J Mendelsohn
Keyword(s):  
Bone Marrow ◽  
Inhibitory Activity ◽  
Polymorphonuclear Leukocytes ◽  
Population Distribution ◽  
Thymidine Uptake ◽  
Allogeneic Bone ◽  
Drug Induced ◽  
Culture Techniques ◽  
Drug Dependent

Two patients with agranulocytosis associated with diphenylhydantoin (DPH) therapy and clinical data suggesting suppression of granulopoiesis were investigated using in vitro culture techniques for committed granulocyte/macrophage precursors. Addition of DPH to cultures containing the patients' sera resulted in significant suppression of colony growth. Extensive studies on the acute serum from one patient revealed the drug-dependent inhibitory activity to be nondialyzable, resistant to chloroform extraction, heat stable, active in the presence of heat-inactivated fetal bovine serum, active against autologous as well as allogeneic cells, and absent from convalescent sera. Drug-dependent bone marrow colony-suppressing activity was removed by absorption on an antiimmunoglobulin-Sepharose column but not by IgG-Sepharose. The serum show non-drug dependent suppression of oxygen consumption by normal polymorphonuclear leukocytes engaged in phagocytosis and also showed evidence of ability to opsonize these cells. When the serum was incubated with mitogen-stimulated lymphocytes, suppression of 3H-thymidine uptake by autologous but not allogeneic cells was noted. Similarly, the serum suppressed short-term 3H-thymidine uptake by autologous but not allogeneic bone marrow. Absorption of the patients' sera with allogeneic polymorphonuclear leukocytes, autologous polymorphonuclear leukocytes, or autologous lymphocytes removed the drug-dependent inhibitory activity, but absorption with allogeneic lymphocytes did not. These data are most consistent with the presence of a noncomplement dependent antibody capable of suppressing granulopoiesis, mediating peripheral destruction of polymorphonuclear leukocytes, and cross-reacting with a lymphocyte antigen of limited population distribution.

scholarly journals Effects of a phytoestrogen-containing soy extract on the growth-inhibitory activity of ICI 182 780 in an experimental model of estrogen-dependent breast cancer

2007 ◽  
Vol 14 (2) ◽  
pp. 317-324 ◽  
Author(s):  
Daniela Gallo ◽  
Elisabetta Mantuano ◽  
Manuela Fabrizi ◽  
Cristiano Ferlini ◽  
Simona Mozzetti ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Inhibitory Activity ◽  
Concomitant Administration ◽  
Breast Cancer Cell Lines ◽  
Concomitant Treatment ◽  
Drug Induced ◽  
Mrna Gene ◽  
Positive Breast Cancer Cell ◽  
Mcf 7

The study reported here was designed to determine whether a phytoestrogen-containing soy extract (SSE) could negate/overwhelm the inhibitory effects of ICI 182 780 on the growth of estrogen-sustained human breast cancer xenografts (MCF-7), in ovariectomized athymic mice. As expected, estradiol-supplemented tumors did not grow over the study period in ICI 182 780-treated females; concomitant administration of 50 mg/kg per day SSE slightly potentiated the inhibitory activity of the drug, while at 100 mg/kg per day, SSE partially negated ICI 182 780 activity. In keeping with these in vivo outcomes, we observed that the level of cyclin D1 (and progesterone receptor) in MCF-7 xenografts was considerably reduced by ICI 182 780, an effect enhanced by concomitant treatment with 50 SSE, but reduced by the higher dosage (i.e. 100 mg/kg per day). Thrombospondin-1 (TSP-1) and kallikrein 6 (KLK6) levels were also reduced following ICI 182 780, although to a lesser degree; again, combined anti-estrogen and SSE produced a dose-dependent regulation in TSP-1 and KLK6 tumor level, with a further reduction in the mRNA gene expression at 50 SSE (compared with ICI 182 780) and a partial reversion of the drug-induced down-regulation at 100 mg/kg per day. No modulation was detected in the serum concentration of IGF-1 (a potent mitogen for estrogen receptor-positive breast cancer cell lines) either upon treatment with ICI 182 780 or concomitant administration of the anti-estrogen with SSE. In conclusion, results from this study raise concerns about the consumption of isoflavone supplements in conjunction with ICI 182 780 therapy, in postmenopausal women with estrogen-dependent breast cancer.

scholarly journals Synthesis, anticancer and FGFR1 inhibitory activity of isoindolo[2,1-a][1,2,4]triazino[2,3-c]quinazoline derivatives

2016 ◽  
Author(s):  
O. Yu. Voskoboynik ◽  
S. A. Starosyla ◽  
M. V. Protopopo ◽  
H. P. Volynets ◽  
S. V. Shyshkina ◽  
...  
Keyword(s):  
Hydrogen Bond ◽  
Acetic Acid ◽  
Inhibitory Activity ◽  
Spectral Properties ◽  
Docking Study ◽  
Benzoic Acids ◽  
Low Field ◽  
Quinazoline Derivatives

Presented manuscript describes the synthesis, antitumor and FGFR1 inhibitory activity of novel isoindolo[2,1-a][1,2,4]triazino[2,3-c]quinazolines. It was shown that mentioned above substances may be prepared by interactionof 3-(2-amino-3-R2-5-R3-phenyl)-6-R1-1,2,4-triazin-5(2H)-ones with 2-formylbenzoic and 6-formyl-2,3-dimethoxybenzoic (opianic) acids in acetic acid. It was shown that proper 2-(2-oxo-3-R-6,7-dihydro-2H-[1,2,4]triazino[2,3-c]quinazolin-6-yl)benzoic acids (or corresponded dimethoxysubstituted analogues) may be considered as intermediates of thereaction. Spectral properties of synthesized compounds were studied, it was shown that protons in position 8 wereobserved at low field as result of the presence of hydrogen bond between hydrogen at position 8 and oxygen atposition 10. The anticancer assay data allowed to identify synthesized compounds as promising antitumor agents.The FGFR1 inhibitory activity of synthesized compounds was detected and docking study aimed to the evaluationof mentioned action was conducted.

scholarly journals Point mutations that inactivate MGAT4D-L, an inhibitor of MGAT1 and complex N-glycan synthesis

2020 ◽  
Vol 295 (41) ◽  
pp. 14053-14064
Author(s):  
Ayodele Akintayo ◽  
Joshua Mayoral ◽  
Masahiro Asada ◽  
Jian Tang ◽  
Subha Sundaram ◽  
...  
Keyword(s):  
Amino Acids ◽  
Inhibitory Activity ◽  
Mammalian Cells ◽  
Point Mutations ◽  
Site Directed Mutagenesis ◽  
Mechanism Of Inhibition ◽  
C Terminus ◽  
Membrane Bound ◽  
Galanthus Nivalis ◽  
Glcnac Transferase

The membrane-bound, long form of MGAT4D, termed MGAT4D-L, inhibits MGAT1 activity in transfected cells and reduces the generation of complex N-glycans. MGAT1 is the GlcNAc-transferase that initiates complex and hybrid N-glycan synthesis. We show here that Drosophila MGAT1 was also inhibited by MGAT4D-L in S2 cells. In mammalian cells, expression of MGAT4D-L causes the substrate of MGAT1 (Man5GlcNAc2Asn) to accumulate on glycoproteins, a change that is detected by the lectin Galanthus nivalis agglutinin (GNA). Using GNA binding as an assay for the inhibition of MGAT1 in MGAT4D-L transfectants, we performed site-directed mutagenesis to determine requirements for MGAT1 inhibition. Deletion of 25 amino acids (aa) from the C terminus inactivated MGAT4D-L, but deletion of 20 aa did not. Conversion of the five key amino acids (PSLFQ) to Ala, or deletion of PSLFQ in the context of full-length MGAT4D-L, also inactivated MGAT1 inhibitory activity. Nevertheless, mutant, inactive MGAT4D-L interacted with MGAT1 in co-immuno-precipitation experiments. The PSLFQ sequence also occurs in MGAT4A and MGAT4B GlcNAc-transferases. However, neither inhibited MGAT1 in transfected CHO cells. MGAT4D-L inhibitory activity could be partially transferred by attaching PSLFQ or the 25-aa C terminus of MGAT4D-L to the C terminus of MGAT1. Mutation of each amino acid in PSLFQ to Ala identified both Leu and Phe as independently essential for MGAT4D-L activity. Thus, replacement of either Leu-395 or Phe-396 with Ala led to inactivation of MGAT4D-L inhibitory activity. These findings provide new insights into the mechanism of inhibition of MGAT1 by MGAT4D-L, and for the development of small molecule inhibitors of MGAT1.

scholarly journals Inhibition of cell-free protein synthesis by low-molecular-weight nuclear polyadenylate-containing ribonucleic acid species isolated from the lactating guinea pig

1980 ◽  
Vol 186 (2) ◽  
pp. 561-570 ◽  
Author(s):  
I C Bathurst ◽  
R K Craig ◽  
P N Campbell
Keyword(s):  
Protein Synthesis ◽  
Mammary Gland ◽  
Germ Cell ◽  
Inhibitory Activity ◽  
Wheat Germ ◽  
Free System ◽  
Cell Free System ◽  
Mechanism Of Inhibition ◽  
Endogenous Activity ◽  
Cell Free Protein Synthesis

1. Poly(A)-containing RNA was isolated from the nuclei of mammary gland, liver and brain of lactating guinea pigs. 2. Total nuclear poly(A)-containing RNA from mammary gland inhibited mRNA-directed protein synthesis by a wheat-germ cell-free system. It also inhibited the endogenous activity of the wheat-germ and other cell-free systems. It did not inhibit a wheat-germ cell-free system directed by poly(U). 3. Total nuclear poly(A)-containing RNA from liver and brain did not inhibit the mRNA-directed wheat-germ system. 4. Fractionation of the nuclear poly(A)-containing RNA revealed inhibitory activity in the less than 10 S fraction from mammary gland as well as that from liver and brain. 5. The mechanism of protein-synthesis inhibition appeared to be at the level of elongation. 6. The inhibitory activity could be reversed in a wheat-germ system by increasing the amount of S-30 supernatant. 7. The mechanism of inhibition of protein synthesis is discussed in relation to other RNA species known to inhibit such systems.

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