Free radicals in biology
Roger L. McMullen in Antioxidants and the Skin, 2018
In general, enzymes can be sources of free radicals as they are often involved in electron transfer reactions, which occasionally result in the leakage of electrons.2 In addition, various enzymes that serve roles as oxidases can potentially be sources of free radical species. Several examples include: D-amino acid oxidase: This enzyme is responsible for the eradication of unwanted amino acids in the cell.Xanthine oxidase: As part of purine metabolism, the degradation of hypoxanthine to xanthine and xanthine to uric acid is achieved by xanthine oxidase (Chapter 3).Nitric oxide synthase: Actually, this is a family of enzymes that is responsible for the synthesis of NO•.Myeloperoxidase: During phagocytosis (already discussed) this enzyme is responsible for the formation of HOCl.NADPH oxidase: As a membrane-bound protein, this enzyme participates in the production of O2•− during phagocytosis.
Micronutrients
Chuong Pham-Huy, Bruno Pham Huy in Food and Lifestyle in Health and Disease, 2022
Molybdenum (Mo) is an essential micro-mineral and acts as a cofactor for the activities of several enzymes in the human body including xanthine oxidase, aldehyde oxidase, sulfite oxidase, nitrate reductase, and hydrogenase (4, 6, 8–9). Xanthine oxidase and aldehyde oxidase play a role in iron utilization as well as in cellular metabolism and electron transport. Xanthine oxidase is also used in the uptake and release of iron from ferritin in the intestinal mucosa and in the release of iron from ferritin in the liver, placenta, and erythropoietic tissues to the ferrous form (8). Xanthine oxidase and hydrogenase play a role in the production of uric acid from hypoxanthine and xanthine (4). Aldehyde oxidase oxidizes and detoxifies purines and pyrimidines, while sulfite oxidase containing molybdenum incorporated as part of the molecule, is used for the conversion of sulfite to sulfate (4).
Micronutrient Supplementation and Ergogenesis — Metabolic Intermediates
Luke Bucci in Nutrients as Ergogenic Aids for Sports and Exercise, 2020
In humans, excess inosine is not converted to adenine nucleotides, but is metabolized by the enzyme xanthine oxidase, a potent generator of Superoxide radicals,578 to uric acid.579,580 In humans, liver and small intestines contain large amounts of xanthine oxidase.581 Importantly, xanthine dehydrogenase in muscle tissue is converted to active xanthine oxidase by ischemia and exercise,350,581,582increasing the formation of free radicals in muscle tissue to a greater extent than explained by resting levels of muscle xanthine oxidase. This mechanism is now thought to be a major generator of exercise-induced free radicals and lipid peroxidation. In fact, plasma inosine, hypoxanthine, and uric acid levels are used as markers for ischemia and anaerobic stress.583–586 Exacerbation of gout by excess purines is also possible after administration of inosine.223,587 Furthermore, oral administration of purine nucleotides (e.g., inosine or adenosine) to rodents reveals substantial degradation by the intestinal mucosa,588 rendering oral supplementation of inosine to have at best, dubious, and at worst, hazardous value to humans.
In vitro enzyme inhibition and in vivo anti-hyperuricemic potential of eugenol: an experimental approach
Published in Drug Development and Industrial Pharmacy, 2021
V. Vijeesh, A. Vysakh, Ninan Jisha, M. S. Latha
The global index of the hyperuricemia incidence has reached 1.13 billion in 2015 [16]. The incidence of hyperuricemia and its associated diseases were increased in many countries during the last decades [17]. When the serum urate levels exceed the normal threshold, it leads to the hyperuricemia [18]. Exogenous purine intake, a source of uric acid production ranges from 100 to 200 mg per day, with the majority of serum uric acid coming from endogenous sources such as nucleic acid breakdown and de novo purine production [19]. That is why the elevated levels of uric acid in an individual with preoperative condition are considered as a potential risk factor for the development of postoperative hyperuricemia linked complications [20]. Hyperuricemia is one of the signs of tumor lysis syndrome [21]. The frequent consumption of organ meat, seafood, alcohol, etc. also increases the risk of hyperuricemia condition [22]. The recent studies proposed that the fructose metabolism, high intracellular glucose and excess fat storage are positively correlated with high level of uric acid production [23–25]. Xanthine oxidase is a therapeutic target in humans because it catalyzes the conversion of purines to uric acid. The hyperuricemia condition can be induced in rat model by inhibiting the uricase enzyme. PO is a well-known uricase inhibiting agent commonly used to induce hyperuricemia condition.
Preparation of an isorhamnetin phospholipid complex for improving solubility and anti-hyperuricemia activity
Published in Pharmaceutical Development and Technology, 2022
Fengmao Zou, Honghui Zhao, Aijinxiu Ma, Danni Song, Xiangrong Zhang, Xu Zhao
Xanthine oxidase (XOD) plays a key role in the metabolism of purines to produce UA. Purine metabolism in the body produces xanthine and hypoxanthine, which are oxidized by XOD to produce UA (Zou et al. 2021). Therefore, screening for XOD inhibitors is one of the main ideas in the treatment of HUA. Our previous studies have demonstrated that ISO has a favorable XOD inhibitory effect. In vitro experiments demonstrated that ISO inhibited XOD by 77.9% and additional in vivo experiments in mice confirmed its effective anti-hyperuricemic activity (Wang et al. 2021). However, the challenging physicochemical properties of ISO have prevented its further development and application. The purpose of our study was to improve the anti-hyperuricemic activity of ISO by improving its solubility by its incorporation into phospholipid complexes.
Recent approaches to gout drug discovery: an update
Published in Expert Opinion on Drug Discovery, 2020
Naoyuki Otani, Motoshi Ouchi, Hideo Kudo, Shuichi Tsuruoka, Ichiro Hisatome, Naohiko Anzai
Considering these challenges, new therapies are needed for patients with hyperuricemia who cannot achieve sufficient urate reduction with current therapies. Recent progress on molecularly targeted therapies has generated interest in drug discovery targeting transporters. Lesinurad is an orally administered selective inhibitor of the kidneys’ URAT1 and OAT4, via which it inhibits urate reabsorption and thus increases renal urate excretion and lowers serum urate levels. Currently, it is indicated for use in combination with a xanthine oxidase inhibitor for the treatment of hyperuricemia associated with gout in patients who have not achieved target serum uric acid levels with a xanthine oxidase inhibitor alone. FYU-981(Dotinurad) is a novel, selective urate reabsorption inhibitor, which reduces serum uric acid levels by selective inhibition of URAT1, and was approved in Japan on November 2019. Possible drug discovery targets include not only URAT1 but also other transporters, such as URATv1/GLUT9 and NPT4. Furthermore, the urate transportsome is pivotal as a new concept for regulating urate excretion; if its functional and molecular characterization progresses, it may also become a new target for drug discovery. Drug discovery targeting other transporters, such as URATv1/GLUT9 and NPT4 are being developed in early phase. However, results from pivotal trials are waited for some novel agents.
Related Knowledge Centers
- Enzyme
- Hypoxanthine
- Purine
- Reactive Oxygen Species
- Uric Acid
- Xanthine
- Aldehyde
- Redox
- Xanthine Dehydrogenase
- Pterin