scholarly journals Role of human glutathione transferases in biotransformation of the nitric oxide prodrug JS-K

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Birgitta Sjödin ◽  
Bengt Mannervik
Keyword(s):  
Nitric Oxide ◽  
Glutathione Transferase ◽  
Specific Activity ◽  
Physiological Role ◽  
Catalytic Efficiency ◽  
Signal Molecule ◽  
Killing Effect ◽  
Normal Tissues ◽  
Tumor Killing

AbstractNitric oxide (NO) plays a prominent physiological role as a low-molecular-mass signal molecule involved in diverse biological functions. Great attention has been directed to pharmacologically modulating the release of NO for various therapeutic applications. We have focused on O2-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K) as an example of diazeniumdiolate prodrugs with potential for cancer chemotherapy. JS-K is reportedly activated by glutathione conjugation by glutathione transferase (GST), but the scope of activities among the numerous members of the GSTome is unknown. We demonstrate that all human GSTs tested except GST T1-1 are active with JS-K as a substrate, but their specific activities are notably spanning a > 100-fold range. The most effective enzyme was the mu class member GST M2-2 with a specific activity of 273 ± 5 µmol min−1 mg−1 and the kinetic parameters Km 63 µM, kcat 353 s−1, kcat/Km 6 × 106 M−1 s−1. The abundance of the GSTs as an ensemble and their high catalytic efficiency indicate that release of NO occurs rapidly in normal tissues such that this influence must be considered in clarification of the tumor-killing effect of JS-K.

scholarly journals Role of Human Glutathione Transferases in Biotransformation of the Nitric Oxide Prodrug JS-K

2021 ◽  
Author(s):  
Birgitta Sjödin ◽  
Bengt Mannervik
Keyword(s):  
Nitric Oxide ◽  
Glutathione Transferase ◽  
Specific Activity ◽  
Physiological Role ◽  
Catalytic Efficiency ◽  
Signal Molecule ◽  
Killing Effect ◽  
Normal Tissues ◽  
Tumor Killing

Abstract Nitric oxide (NO) plays a prominent physiological role as a low-molecular-mass signal molecule involved in diverse biological functions. Great attention has been directed to pharmacologically modulating the release of NO for various therapeutic applications. We have focused on O2-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K) as an example of diazeniumdiolate prodrugs with potential for cancer chemotherapy. JS-K is reportedly activated by glutathione conjugation by glutathione transferase (GST), but the scope of activities among the numerous members of the GSTome is unknown. We demonstrate that all human GSTs tested except GST T1-1 are active with JS-K as a substrate, but their specific activities are notably spanning a 100-fold range. The most effective enzyme was the mu class member GST M2-2 with a specific activity of 273 ± 5 µmol min-1 mg-1 and the kinetic parameters Km 48 ± 4 µM, kcat 501 ± 29 s-1, kcat/Km 10 x106 M-1 s-1. The abundance of the GSTs as an ensemble and their high catalytic efficiency indicate that release of NO occurs rapidly in normal tissues such that other mechanisms play a major role in the tumor-killing effect of JS-K.

scholarly journals Regulation of nitric oxide synthase isoforms and role of nitric oxide during prostaglandin F2alpha-induced luteolysis in rabbits

Reproduction ◽  
2003 ◽  
pp. 807-816 ◽  
Author(s):  
C Boiti ◽  
G Guelfi ◽  
D Zampini ◽  
G Brecchia ◽  
A Gobbetti ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Time Course ◽  
Plasma Concentrations ◽  
Physiological Role ◽  
Total Activity ◽  
Corpora Lutea ◽  
Prostaglandin F ◽  
Oxide Synthase

Total activity of nitric oxide synthase (NOS) and the gene expression of both endothelial NOS (eNOS) and inducible NOS (iNOS) isoforms in corpora lutea of pseudopregnant rabbits were examined during prostaglandin F(2alpha) (PGF(2alpha))-induced luteolysis. Corpora lutea were collected at 0, 6, 12, 24 and 48 h after an injection of PGF(2alpha) at day 9 of pseudopregnancy. At 12 h after PGF(2alpha) administration, luteal mRNA encoding eNOS decreased (P0.05) by 40% and remained low throughout the subsequent 36 h, whereas eNOS protein increased (P0.05) two- to threefold. By contrast, expression of mRNA encoding iNOS was poor and remained fairly constant, but transcription increased eightfold (P0.01) within 6 h after PGF(2alpha) treatment and then decreased to values similar to those of controls. Total NOS activity increased twofold (P0.01) at 6 h after treatment and remained high thereafter, whereas progesterone concentrations in explanted corpora lutea decreased (P0.01) from 302.4+/-42.3 pg x mg(-1) at day 9 to 58.6+/-8.3 at 48 h later, and peripheral plasma concentrations of progesterone declined too. Long-term administration of Nomega-nitro-L-arginine methyl ester (0.6 g l(-1) per os) from day 2 of pseudopregnancy onward partially blocked the luteolytic action of PGF(2alpha) administered at day 9 of pseudopregnancy. In nitric oxide (NO)-deficient rabbits, progesterone concentrations remained higher (P0.01) than in controls at 24-48 h after PGF(2alpha) administration (4.5 to 3.2 ng x ml(-1), respectively). These data are the first to characterize NOS activity. The time course of expression of eNOS and iNOS in rabbit corpora lutea during PGF(2alpha)-induced luteolysis gives additional support to a physiological role of NO in the regulation of regression of corpora lutea in rabbits.

scholarly journals The Critical Role of Tetrahydrobiopterin (BH4) Metabolism in Modulating Radiosensitivity: BH4/NOS Axis as an Angel or a Devil

2021 ◽  
Vol 11 ◽  
Author(s):  
Yang Feng ◽  
Yahui Feng ◽  
Liming Gu ◽  
Pengfei Liu ◽  
Jianping Cao ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Free Radicals ◽  
Ionizing Radiation ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Antiangiogenic Therapy ◽  
Critical Role ◽  
Cellular Radiosensitivity ◽  
Normal Tissues

Ionizing radiation and radioactive materials have been widely used in industry, medicine, science and military. The efficacy of radiotherapy and adverse effects of normal tissues are closed related to cellular radiosensitivity. Molecular mechanisms underlying radiosensitivity are of significance to tumor cell radiosensitization as well as normal tissue radioprotection. 5,6,7,8-Tetrahydrobiopterin (BH4) is an essential cofactor for nitric oxide synthases (NOS) and aromatic amino acid hydroxylases, and its biosynthesis involves de novo biosynthesis and a pterin salvage pathway. In this review we overview the role of BH4 metabolism in modulating radiosensitivity. BH4 homeostasis determines the role of NOS, affecting the production of nitric oxide (NO) and oxygen free radicals. Under conditions of oxidative stress, such as UV-radiation and ionizing radiation, BH4 availability is diminished due to its oxidation, which subsequently leads to NOS uncoupling and generation of highly oxidative free radicals. On the other hand, BH4/NOS axis facilitates vascular normalization, a process by which antiangiogenic therapy corrects structural and functional flaws of tumor blood vessels, which enhances radiotherapy efficacy. Therefore, BH4/NOS axis may serve as an angel or a devil in regulating cellular radiosensitivity. Finally, we will address future perspectives, not only from the standpoint of perceived advances in treatment, but also from the potential mechanisms. These advances have demonstrated that it is possible to modulate cellular radiosensitivity through BH4 metabolism.

Physiological Role of Nitric Oxide in Gallbladder Emptying in Men

Digestion ◽  
1997 ◽  
Vol 58 (4) ◽  
pp. 373-378 ◽  
Author(s):  
J.W. Konturek ◽  
S.J. Konturek ◽  
T. Pawlik ◽  
W. Domschke
Keyword(s):  
Nitric Oxide ◽  
Physiological Role ◽  
Gallbladder Emptying

The physiological role of nitric oxide

1993 ◽  
Vol 22 (4) ◽  
pp. 233 ◽  
Author(s):  
Anthony R. Butler ◽  
D. Lyn H. Williams
Keyword(s):  
Nitric Oxide ◽  
Physiological Role

scholarly journals Inducible nitric oxide synthase provides protection against injury-induced thrombosis in female mice

2011 ◽  
Vol 301 (2) ◽  
pp. H617-H624 ◽  
Author(s):  
Rita K. Upmacis ◽  
Hao Shen ◽  
Lea Esther S. Benguigui ◽  
Brian D. Lamon ◽  
Ruba S. Deeb ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Ex Vivo ◽  
Physiological Role ◽  
Thrombotic Occlusion ◽  
Female Mice ◽  
Eicosanoid Production ◽  
Oxide Synthase ◽  
Deficient Mice ◽  
Inducible Nitric Oxide

Nitric oxide (NO) is an important vasoactive molecule produced by three NO synthase (NOS) enzymes: neuronal (nNOS), inducible (iNOS), and endothelial NOS (eNOS). While eNOS contributes to blood vessel dilation that protects against the development of hypertension, iNOS has been primarily implicated as a disease-promoting isoform during atherogenesis. Despite this, iNOS may play a physiological role via the modulation of cyclooxygenase and thromboregulatory eicosanoid production. Herein, we examined the role of iNOS in a murine model of thrombosis. Blood flow was measured in carotid arteries of male and female wild-type (WT) and iNOS-deficient mice following ferric chloride-induced thrombosis. Female WT mice were more resistant to thrombotic occlusion than male counterparts but became more susceptible upon iNOS deletion. In contrast, male mice (with and without iNOS deletion) were equally susceptible to thrombosis. Deletion of iNOS was not associated with a change in the balance of thromboxane A2 (TxA2) or antithrombotic prostacyclin (PGI2). Compared with male counterparts, female WT mice exhibited increased urinary nitrite and nitrate levels and enhanced ex vivo induction of iNOS in hearts and aortas. Our findings suggest that iNOS-derived NO in female WT mice may attenuate the effects of vascular injury. Thus, although iNOS is detrimental during atherogenesis, physiological iNOS levels may contribute to providing protection against thrombotic occlusion, a phenomenon that may be enhanced in female mice.

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