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Micronutrient Supplementation and Ergogenesis — Metabolic Intermediates
Published in Luke Bucci, Nutrients as Ergogenic Aids for Sports and Exercise, 2020
A study measured swimming performance of mice after administration of synthetic spin-trappers (compounds that directly neutralize free radicals) N-t-butyl-α-phenyl-nitrone (PBN), 5,5-dimethyl- 1-pirrolyn-N-oxide (DMPO), and α-4-pyridyl-1-oxide-N-t-butyl-nitrone (POBN).340 Significantly improved swimming times (298 vs. 398,493, and 555 sec after PBN, POBN and DMPO, respectively) were found, indicating that removal of free radicals would enhance aerobic performance.340 Similarly, after rats were injected with the synthetic antioxidant BHT (20 mg/kg/d for 3 d), a 60% increase in maximum duration of treadmill running to exhaustion was found.442 In addition, lipid peroxide levels in muscles were significantly lower at time of exhaustion after BHT supplementation.
Xenobiotic Biotransformation
Published in Robert G. Meeks, Steadman D. Harrison, Richard J. Bull, Hepatotoxicology, 2020
The enzyme is characterized by large species differences in activity; activities are high in hogs, dogs, guinea pigs, and humans. The reaction mechanism involves a hydroperoxyflavin as oxygenating intermediate with oxygen transfer from the hydroperoxyflavin to the substrate. FMO only catalyzes the oxidation of nitrogen compounds bearing functional groups that are readily oxidized by organic peroxides. The hydroperoxyflavin will not attack nitrogen atoms in amides, carbamides, imines, nitrones, oximes, isocynates, nitriles, or heterocyclic aromatic amines. Amines, hydroxylamines, and hydrazines are excellent substrates. The thermal lability of the liver enzyme has been utilized to distinguish it from P450-linked enzyme. There are no known inhibitors of the FMO; however, methimazole (a substrate) has been utilized as a competitive inhibitor to differentiate between P450 and FMO activities. The purified liver enzyme appears to have one binding site for activators, which appear to be positively charged lipophilic compounds such as primary alkylamines (n-octylamine is the prototype) or alkyl guanidines. The enzyme is not inducible by xenobiotics; activity is actually reduced by PB, β-NF, or PAH treatment. Hormones appear to exert an important regulatory control on FMO activity.
Metabolic Activation of Aromatic Amines and Amides and Interactions with Nucleic Acids
Published in Philip L. Grover, Chemical Carcinogens and DNA, 2019
A well-documented example of N-oxidation of an arylamine as a first activation step is the hepatocarcinogen N-methyl-4-aminoazobenzene. Nucleoside derivatives isolated from hydrolysates of hepatic RNA and DNA from rats to which MAB has been administered have been characterized in Miller’s laboratory by using the guanosine derivatives prepared by reaction with the synthetic ester N-benzoyloxy-MAB.60-62 The recent chemical synthesis of N-hydroxy-MAB by Kadlubar et al.63 enabled a study of metabolic formation and subsequent esterification to be made. Incubation of MAB with rat-liver microsomes and a NADPH-generating system yielded both 4-aminoazoben-zene (AB) and N-hydroxy-AB, as illustrated in Figure 3. The microsomal demethyla-tion by the mixed-function oxidase system is a well-established reaction.64N-oxidation of the primary amine (AB) is consistent with the detection of a conjugate of N-acetyl-N-hydroxy-AB as an urinary metabolite of AB, MAB, and DAB.65 In a recent study, Kadlubar et al.63 demonstrated the formation of N-hydroxy-MAB in the microsomal oxidation of MAB by isolating the nitrone (Figure 3) through extraction with an organic solvent. The nitrone decomposes nonenzymically, in an acid-catalyzed reaction, to N-hydroxy-MAB. In addition, Kadlubar et al.63 showed that N-hydroxy-MAB is activated in a PAPS-dependent reaction by rat-liver cytosol in a similar manner to N-hydroxy-AAF.
Emerging clinical investigational drugs for the treatment of amyotrophic lateral sclerosis
Published in Expert Opinion on Investigational Drugs, 2023
Loreto Martinez-Gonzalez, Ana Martinez
Another process that has been targeted during years as a therapeutic strategy for ALS is oxidative stress (Table 1, Figure 2). Tetramethylpyrazine nitrone (NCT04667013), a small molecule also known as TBN, is being investigated to evaluate its safety, tolerability and pharmacokinetic properties in healthy participants. The investigational drug has shown strong free radical scavenging ability. The antioxidant effects of TBN are mediated via activation of the AMPK/PGC-1/Nrf2/HO-1 signaling pathway [21]. The ALS mouse model carrying a mutation (G93A) in the superoxide dismutase 1 protein (SOD1G93A) was used to investigate the efficacy of TBN. It was administered to mice by intraperitoneal or intragastric injection after the onset of motor deficits slowing the progression of motor neuron disease. Improvement of motor performance, decrease of spinal motor neuron loss, the associated glial response, and skeletal muscle fiber denervation was observed. More recently, the same phenotypic and biochemical behavior have been obtained in mice with bilateral injection of transactive response DNA-binding protein 43 (TDP-43) with the mutation M337V (TDP-43M337V) into the striatum [22]. All these data point to TBN as a promising agent for the treatment of ALS and frontotemporal lobar degeneration (FTLD).
Research progress in strategies to improve the efficacy and safety of doxorubicin for cancer chemotherapy
Published in Expert Review of Anticancer Therapy, 2021
Muhammad Sohail, Zheng Sun, Yanli Li, Xuejing Gu, Hui Xu
Nitrones are the compounds of N-oxide amines once used to trap free radicals in chemical systems are now considered to have potential in the treatment of neurodegenerative diseases and some other diseases, such as Alzheimer’s disease, stroke, and the development of cancer [102]. Nitrones can potentially help in decreasing oxidative stress, limiting oxidative damage, and also show anti-inflammatory activity in animal models by altering cellular signaling processes [103]. As the researchers focused on reducing the toxicity of DOX, they tried to use DOX with such agents that limit the toxicity effect of doxorubicin. Gerland et al (US-9061038-B2) patented a method in which he used DOX active agent in combination with nitrone or nitrone compounds which act as DOX toxicity-reducing adjuvant. The above method of doxorubicin in conjunction with nitrone or its compounds were found useful in a variety of different applications, and treatment of a variety of different disease condition [104]. Gerland et al registered another patent (US-8227517-B2) about the same active DOX and DOX toxicity reducing adjuvant (nitrone). In this work, different cell lines (Human T-ALL, CCL-119), and the study was also carried out on mice, the result revealed that the toxicity of DOX was reduced to a larger extent by using the invented formulation [105].