DOCSLIB.ORG

Mechanism of Action of N-Acetylcysteine in the Protection Against the Hepatotoxicity of Acetaminophen in Rats in Vivo

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Mechanism of Action of N-Acetylcysteine in the Protection Against the Hepatotoxicity of Acetaminophen in Rats in Vivo Mechanism of Action of N-Acetylcysteine in the Protection Against the Hepatotoxicity of Acetaminophen in Rats In Vivo BERNHARD H. LAUTERBURG, GEORGE B. CORCORAN, and JERRY R. MITCHELL, Baylor College of Medicine, Department of Internal Medicine, Sections on Gastroenterology and Clinical Pharmacology, Houston, Texas 77030 A B S T R A C T N-Acetylcysteine is the drug of choice exogenous N-acetylcysteine significantly increased the for the treatment of an acetaminophen overdose. It is formation of the acetaminophen-glutathione adduct thought to provide cysteine for glutathione synthesis from 57 to 105 nmol/min per 100 g. Although the ex- and possibly to form an adduct directly with the toxic cretion of acetaminophen sulfate increased from 85±15 metabolite of acetaminophen, N-acetyl-p-benzoqui- to 211±17 iimol/100 g per 24 h after N-acetylcysteine, noneimine. However, these hypotheses have not been kinetic simulations showed that increased sulfation tested in vivo, and other mechanisms of action such does not significantly decrease formation of the toxic as reduction of the quinoneimine might be responsible metabolite. Reduction of the benzoquinoneimine by for the clinical efficacy of N-acetylcysteine. After the N-acetylcysteine should result in the formation of N- administration to rats of acetaminophen (1 g/kg) in- acetylcysteine disulfides and glutathione disulfide via traduodenally (i.d.) and of [35S]-N-acetylcysteine (1.2 thiol-disulfide exchange. Acetaminophen alone de- g/kg i.d.), the specific activity of the N-acetylcysteine pleted intracellular glutathione, and led to a progres- adduct of acetaminophen (mercapturic acid) isolated sive decrease in the biliary excretion of glutathione from urine and assayed by high pressure liquid chro- and glutathione disulfide. N-Acetylcysteine alone did matography averaged 76±6% of the specific activity not affect the biliary excretion of glutathione disulfide. of the glutathione-acetaminophen adduct excreted in However, when administered after acetaminophen, N- bile, indicating that virtually all N-acetylcysteine- acetylcysteine produced a marked increase in the bil- acetaminophen originated from the metabolism of the iary excretion of glutathione disulfide from 1.2±0.3 glutathione-acetaminophen adduct rather than from nmol/min per 100 g in control animals to 5.7±0.8 a direct reaction with the toxic metabolite. N-Acetyl- nmol/min per 100 g. Animals treated with acetamin- cysteine promptly reversed the acetaminophen-in- ophen and N-acetylcysteine excreted 2.7±0.8 nmol/ duced depletion of glutathione by increasing gluta- min per 100 g of N-acetylcysteine disulfides (measured thione synthesis from 0.54 to 2.69 gmol/g per h. Ex- by high performance liquid chromatography) com- ogenous N-acetylcysteine did not increase the formation pared to 0.4±0.1 nmol/min per 100 g in rats treated of the N-acetylcysteine and glutathione adducts of with N-acetylcysteine alone. In conclusion, exogenous acetaminophen in fed rats. However, when rats were N-acetylcysteine does not form significant amounts of fasted before the administration of acetaminophen, conjugate with the reactive metabolite of acetamino- thereby increasing the stress on the glutathione pool, phen in the rat in vivo but increases glutathione syn- thesis, thus providing more substrate for the detoxi- Dr. Lauterburg is a recipient of a Pharmaceutical Man- fication of the reactive metabolite in the early phase ufacturers Association Foundation Faculty Development of an acetaminophen intoxication when the critical Award in Clinical Pharmacology. reaction with vital macromolecules occurs. Address reprint requests to Dr. Lauterburg. Dr. Mitchell is a Burroughs Wellcome Scholar in Clinical Pharmacology. Dr. Corcoran is now located at the Department of Phar- INTRODUCTION maceutics, The State University of New York at Buffalo, Amherst, NY 14260. N-Acetylcysteine and other sulfhydryl donors such as Received for publication 24 February 1982 and in revised cysteine, methionine, and cysteamine have been shown form 29 November 1982. to be effective antidotes protecting against the hepa- 980 J. Clin. Invest. © The American Society for Clinical Investigation, Inc. * 0021-9738/83/04/0980/12 $1.00 Volume 71 April 1983 980-991 totoxicitv of acetaminophen both in animal models As a third possibility, N-acetylcysteine might protect (1-4) and clinical practice (a, 6). Because of its ease by increasing the availability of inorganic sulfate, thus of administration and low toxicity, N-acetylcvsteine increasing the formation of acetaminophen-sulfate is currently the favorite compound for the treatment and simultaneously decreasing the fraction of acet- of acetaminophen overdose in man (6, 7). Despite its amninophen metabolized to the toxic intermiedi- widespread clinical use, however, the mechanism(s) ate (16). of action of N-acetvlcvsteine in vivo remain to be (1em- Fourthlv, N-acetylcysteine could reduce the reac- onstrated. tive intermediate of acetaminophen, N-acetyl-p-ben- N-Acetvlcvsteine could conceivably protect against zoquinoneimine, back to acetaminophen, thereby pre- the hepatotoxicity of acetaminophen in several ways. venting its reaction with glutathione and vital mac- First, N-acetvlcvsteine ma) serve as a precursor for romolecules. We have recently demonstrated that the glutathione synthesis. Glutathione plays a critical role reduction of the reactive metabolite by cysteine or in the protection against hepatic necrosis produced by ascorbic acid is a quantitatively important reaction in acetaminophen (1). Hepatocellular necrosis occurs vitro and prevents covalent binding of the toxic in- only when the hepatic content of glutathione falls be- termediate to microsomal proteins (17). low a critical threshold concentration (1). A stimula- From data obtained mostly in vitro, therefore, a tion of glutathione synthesis following the administra- number of potential mechanisms of action of N-ace- tion of N-acetylcysteine and thus a greater availability tvleysteine have been demonstrated. However, these of glutathione for the detoxification of the toxic acet- mechanistic studies have not evaluated the importance aminophen intermediate should protect against liver of the potential interactions of N-acetylcvsteine with injury. In isolated hepatocytes, N-acetylcysteine is in- the toxic process in vivo. To elucidate the mechanism deed capable of supporting glutathione synthesis when of action in vivo, we have administered radioactively it is the only source of cysteine (8). However, in iso- labeled N-acetvlcysteine together with acetaminophen lated cells incubated with acetaminophen, very high to rats to determine the contribution of exogenous N- concentrations of N-acetylcysteine or preincubation acetyrlcsteine to the formation of the N-acetylcvsteine with the sulfhvdrvl are required to increase the for- alduct of acetaminophen (mercapturic acid) following mation of acetaminophen-glutathione (9). Our recent a toxic dose of acetaminophen. In addition, we have studies of glutathione kinetics following a toxic dose tested the hypothesis that N-acetylcysteine may pro- of acetaminophen further questioned the importance tect by reducing the toxic metabolite of acetamino- of this mechanism of action (10). The synthesis of glu- phen. tathione following a large dose of acetaminophen was found to be suppressed, rather than stimulated, as one METHODS would expect from a depletion of hepatic glutathione (11). Furthermore, some investigators have reported [35S]-N-Acetyl-L-cvsteine was prepared by treating [3S]iJ cys tine (11.4 mCi/mmol, Amersham Corp., Arlington Heights, that N-acetylcysteine does not prevent the acetamin- IL) with two equivalents of acetic anhydride and reducing ophen-induced depletion of glutathione suggesting the peracetylated disulfide intermediate with zinc and acetic that the antidote does not support glutathione synthesis acid according to the method of Sheffner et al. (18). Follow- in vivo (12). ing the addition of unlabeled compound (Sigma Chemical A Co., St. Louis, MO), [355]-N-acetylcysteine was recrystallized second potential mechanism of action is direct from water to a constant specific activity (58.1 dpm/nmol). adduct formation between N-acetylcysteine and the Radiochemical purity exceeded 99% judging from thin-layer reactive intermediate of acetaminophen, thereby pre- chromatography(of the material on Avicel (Analtech Inc., venting covalent binding and cell injurv. In micro- Newark, DE) developed in n-butanol/acetic acid,/w ater, somal incubations, the reactive metabolite of acet- 4:1:1 (retardation factor, Rf, 0.61). The aqueous portion of the mobile phase also contained 1 g/liter Na2EDTA and 0.1 aminophen indeed readily forms adducts with a galiter KCN to inhibit metal-catalyzed oxidation of thi- variety of sulfhvdrvl anions including the N- ols (18). acetylcysteine anion (13). However, the incubation of In order to test the hypothesis that N-acetvlcysteine pro- isolated mouse hiepatocytes with acetaminophen and tects in vivo by formation of an adduct with the reactive N-acetyslcsteine does not result in the formation of intermediate of acetaininophen we compared the specific activities of the glutathione adduct excreted in bile and the the N-acetvlcvsteine adduct of acetaminiophen (8, 9). N-acetylcvsteine adduct (mercapturic acid) excreted in In vivo, the administration of N-acetylcysteine only urine with the specific activity of the administered N-ace- moderately increases the formation of the N-acetvl- tvlcvsteine. Male Sprague
Load more

Recommended publications
  • Acetadote (Acetylcysteine) Injection Is Available As a 20% Solution in 30 Ml (200Mg/Ml) Single Dose Glass Vials
    NDA 21-539/S-004 Page 3 Acetadote® (acetylcysteine) Injection Package Insert NDA 21-539/S-004 Page 4 RX ONLY PRESCRIBING INFORMATION ACETADOTE® (acetylcysteine) Injection For Intravenous Use DESCRIPTION Acetylcysteine injection is an intravenous (I.V.) medication for the treatment of acetaminophen overdose. Acetylcysteine is the nonproprietary name for the N-acetyl derivative of the naturally occurring amino acid, L-cysteine (N-acetyl-L-cysteine, NAC). The compound is a white crystalline powder, which melts in the range of 104° to 110°C and has a very slight odor. The molecular formula of the compound is C5H9NO3S, and its molecular weight is 163.2. Acetylcysteine has the following structural formula: H CH3 N SH O COOH Acetadote is supplied as a sterile solution in vials containing 20% w/v (200 mg/mL) acetylcysteine. The pH of the solution ranges from 6.0 to 7.5. Acetadote contains the following inactive ingredients: 0.5 mg/mL disodium edetate, sodium hydroxide (used for pH adjustment), and Sterile Water for Injection, USP. CLINICAL PHARMACOLOGY Acetaminophen Overdose: Acetaminophen is absorbed from the upper gastrointestinal tract with peak plasma levels occurring between 30 and 60 minutes after therapeutic doses and usually within 4 hours following an overdose. It is extensively metabolized in the liver to form principally the sulfate and glucoronide conjugates which are excreted in the urine. A small fraction of an ingested dose is metabolized in the liver by isozyme CYP2E1 of the cytochrome P-450 mixed function oxidase enzyme system to form a reactive, potentially toxic, intermediate metabolite. The toxic metabolite preferentially conjugates with hepatic glutathione to form nontoxic cysteine and mercapturic acid derivatives, which are then excreted by the kidney.
    [Show full text]
  • The Promise of N-Acetylcysteine in Neuropsychiatry
    Review The promise of N-acetylcysteine in neuropsychiatry 1,2,3,4 5,6 1 1,2,4 Michael Berk , Gin S. Malhi , Laura J. Gray , and Olivia M. Dean 1 School of Medicine, Deakin University, Geelong, Victoria, Australia 2 Department of Psychiatry, University of Melbourne, Parkville, Victoria, Australia 3 Orygen Research Centre, Parkville, Victoria, Australia 4 The Florey Institute of Neuroscience and Mental Health, Victoria, Australia 5 Discipline of Psychiatry, Sydney Medical School, University of Sydney, Sydney, Australia 6 CADE Clinic, Department of Psychiatry, Level 5 Building 36, Royal North Shore Hospital, St Leonards, 2065, Australia N-Acetylcysteine (NAC) targets a diverse array of factors with the pathophysiology of a diverse range of neuropsy- germane to the pathophysiology of multiple neuropsy- chiatric disorders, including autism, addiction, depression, chiatric disorders including glutamatergic transmission, schizophrenia, bipolar disorder, and Alzheimer’s and Par- the antioxidant glutathione, neurotrophins, apoptosis, kinson’s diseases [3]. Determining precisely how NAC mitochondrial function, and inflammatory pathways. works is crucial both to understanding the core biology This review summarises the areas where the mecha- of these illnesses, and to opening the door to other adjunc- nisms of action of NAC overlap with known pathophysi- tive therapies operating on these pathways. The current ological elements, and offers a pre´ cis of current literature article will initially review the possible mechanisms of regarding the use of NAC in disorders including cocaine, action of NAC, and then critically appraise the evidence cannabis, and smoking addictions, Alzheimer’s and Par- that suggests it has efficacy in the treatment of neuropsy- kinson’s diseases, autism, compulsive and grooming chiatric disorders.
    [Show full text]
  • Mechanistic Insights on the Reduction of Glutathione Disulfide by Protein Disulfide Isomerase
    Mechanistic insights on the reduction of glutathione disulfide by protein disulfide isomerase Rui P. P. Nevesa, Pedro Alexandrino Fernandesa, and Maria João Ramosa,1 aUnidade de Ciências Biomoleculares Aplicadas, Rede de Química e Tecnologia, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, 4169-007 Porto, Portugal Edited by Donald G. Truhlar, University of Minnesota, Minneapolis, MN, and approved May 9, 2017 (received for review November 22, 2016) We explore the enzymatic mechanism of the reduction of glutathione of enzymes, which are responsible for the reduction and isomer- disulfide (GSSG) by the reduced a domain of human protein disulfide ization of disulfide bonds, through thiol-disulfide exchange. isomerase (hPDI) with atomistic resolution. We use classical molecular dynamics and hybrid quantum mechanics/molecular mechanics cal- Structure and Function of PDI culations at the mPW1N/6–311+G(2d,2p):FF99SB//mPW1N/6–31G(d): Human protein disulfide isomerase (hPDI) is a U-shaped enzyme FF99SB level. The reaction proceeds in two stages: (i) a thiol-disulfide with 508 residues. Its tertiary structure is composed of four exchange through nucleophilic attack of the Cys53-thiolate to the thioredoxin-like domains (a, b, b′,anda′) and a fifth tail-shaped c GSSG-disulfide followed by the deprotonation of Cys56-thiol by domain (Fig. 1) (14, 15). The maximum activity of hPDI is observed Glu47-carboxylate and (ii) a second thiol-disulfide exchange between when all domains of PDI contribute synergistically to its function (16). the Cys56-thiolate and the mixed disulfide intermediate formed in Similar to thioredoxin, the a and a′ domains have a catalytic the first step.
    [Show full text]
  • (Acetylcysteine) Effervescent Tablets for Oral Solution Intratracheal Instillation Initial U.S
    HIGHLIGHTS OF PRESCRIBING INFORMATION • See the Full Prescribing Information for instructions on how to use the These highlights do not include all the information needed to use nomogram to determine the need for loading and maintenance dosing. CETYLEV® safely and effectively. See full prescribing information for CETYLEV. Recommended Adult and Pediatric Dosage (2.3): • CETYLEV is for oral administration only; not for nebulization or CETYLEV (acetylcysteine) effervescent tablets for oral solution intratracheal instillation Initial U.S. Approval: 1963 • Loading dose: 140 mg/kg • Maintenance doses: 70 mg/kg repeated every 4 hours for a total of 17 ----------------------------INDICATIONS AND USAGE--------------------------- doses. CETYLEV is an antidote for acetaminophen overdose indicated to prevent or • lessen hepatic injury after ingestion of a potentially hepatotoxic quantity of See Full Prescribing Information for weight-based dosage and preparation acetaminophen in patients with acute ingestion or from repeated and administration instructions. supratherapeutic ingestion. (1) Repeated Supratherapeutic Acetaminophen Ingestion (2.4): -----------------------DOSAGE AND ADMINISTRATION----------------------- • Obtain acetaminophen concentration and other laboratory tests to guide Pre-Treatment Assessment Following Acute Ingestion (2.1): treatment; Rumack-Matthew nomogram does not apply. Obtain a plasma or serum sample to assay for acetaminophen concentration at least 4 hours after ingestion. ----------------------DOSAGE FORMS AND STRENGTHS---------------------
    [Show full text]
  • A Randomized Placebo-Controlled Trial of N-Acetylcysteine for Cannabis Use Disorder in Adults
    HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Drug Alcohol Manuscript Author Depend. Author Manuscript Author manuscript; available in PMC 2018 August 01. Published in final edited form as: Drug Alcohol Depend. 2017 August 01; 177: 249–257. doi:10.1016/j.drugalcdep.2017.04.020. A randomized placebo-controlled trial of N-acetylcysteine for cannabis use disorder in adults Kevin M. Graya, Susan C. Sonnea, Erin A. McClurea, Udi E. Ghitzab, Abigail G. Matthewsc, Aimee L. McRae-Clarka, Kathleen M. Carrolld, Jennifer S. Pottere, Katharina Wiestf, Larissa J. Mooneyg, Albert Hassong, Sharon L. Walshh, Michelle R. Lofwallh, Shanna Babalonish, Robert W. Lindbladc, Steven Sparenborgb,†, Aimee Wahlec, Jacqueline S. Kingc, Nathaniel L. Bakera, Rachel L. Tomkoa, Louise F. Haynesa, Ryan G. Vandreyi, and Frances R. Levinj aMedical University of South Carolina, Charleston SC bNational Institute on Drug Abuse Center for the Clinical Trials Network, Rockville MD cThe Emmes Corporation, Rockville MD dYale University, New Haven CT Correspondence: Kevin M. Gray, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, 67 President Street, MSC861, Charleston, SC USA 29425, Phone: (843) 792-6330, Fax: (843) 792-8206, [email protected]. †Retired Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
    [Show full text]
  • Degradation of Glutathione in Plant Cells
    Degradation of Glutathione in Plant Cells: Evidence against the Participation of a y-Glutamyltranspeptidase Reinhard Steinkamp and Heinz Rennenberg Botanisches Institut der Universität zu Köln, Gyrhofstr. 15, D-5000 Köln 41, Bundesrepublik Deutschland Z. Naturforsch. 40c, 29 — 33 (1985); received August 31/October 4, 1984 Tobacco, Glutathione Catabolism, y-Glutamylcysteine, y-Glutamyltranspeptidase, y-Glutamyl- cyclotransferase When y-glutamyltranspeptidase activity in tobacco cells was measured using the artificial substrate y-glutamyl-/?-nitroanilide, liberation of p-nitroaniline was not reduced, but stimulated by addition of glutathione. Therefore, glutathione was not acting as a donator, but as an acceptor of y-glutamyl moieties in the assay mixture, suggesting that y-glutamyltranspeptidase is not participating in degradation of glutathione. Feeding experiments with [^S-cysJglutathione sup­ ported this conclusion. When tobacco cells were supplied with this peptide as sole sulfur source, glutathione and y-glutamylcysteine were the only labelled compounds found inside the cells. The low rate of uptake of glutathione apparently prevented the accumulation of measurable amounts of radioactivity in the cysteine pool. A y-glutamylcyclotransferase, responsible for the conversion of y-glutamylcysteine to 5-oxo-proline and cysteine was found in ammonium sulfate precipitates of tobacco cell homogenates. The enzyme showed high activities with y-glutamylmethionine and y-glutamylcysteine, but not with other y-glutamyldipeptides or glutathione. From these and previously published experiments [(Rennenberg et al., Z. Naturforsch. 3 5 c, 70 8 -7 1 1 (1980)], it is concluded that glutathione is degraded in tobacco cells via the following pathway: y-glu-cys- gly —> y-glu-cys ->• 5-oxo-proline -* glu. Introduction the cysteine conjugate by the action of a y-gluta­ myltranspeptidase (Fig.
    [Show full text]
  • NAC and Vitamin D Restore CNS Glutathione in Endotoxin-Sensitized Neonatal Hypoxic-Ischemic Rats
    antioxidants Article NAC and Vitamin D Restore CNS Glutathione in Endotoxin-Sensitized Neonatal Hypoxic-Ischemic Rats Lauren E. Adams 1,†, Hunter G. Moss 2,† , Danielle W. Lowe 3,† , Truman Brown 2, Donald B. Wiest 4, Bruce W. Hollis 1, Inderjit Singh 1 and Dorothea D. Jenkins 1,* 1 Department of Pediatrics, 10 McLellan Banks Dr, Medical University of South Carolina, Charleston, SC 29425, USA; [email protected] (L.E.A.); [email protected] (B.W.H.); [email protected] (I.S.) 2 Center for Biomedical Imaging, Department of Radiology, Medical University of South Carolina, 68 President St. Room 205, Charleston, SC 29425, USA; [email protected] (H.G.M.); [email protected] (T.B.) 3 Department of Psychiatry, Medical University of South Carolina, 67 Presidents St., MSC 861, Charleston, SC 29425, USA; [email protected] 4 Department of Pharmacy and Clinical Sciences, College of Pharmacy, Medical University of South Carolina, Charleston, SC 29425, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-843-792-2112 † Three first authors contributed equally to this work. Abstract: Therapeutic hypothermia does not improve outcomes in neonatal hypoxia ischemia (HI) complicated by perinatal infection, due to well-described, pre-existing oxidative stress and neuroin- flammation that shorten the therapeutic window. For effective neuroprotection post-injury, we must first define and then target CNS metabolomic changes immediately after endotoxin-sensitized HI (LPS-HI). We hypothesized that LPS-HI would acutely deplete reduced glutathione (GSH), indicating overwhelming oxidative stress in spite of hypothermia treatment in neonatal rats. Post-natal day 7 Citation: Adams, L.E.; Moss, H.G.; rats were randomized to sham ligation, or severe LPS-HI (0.5 mg/kg 4 h before right carotid artery Lowe, D.W.; Brown, T.; Wiest, D.B.; ligation, 90 min 8% O2), followed by hypothermia alone or with N-acetylcysteine (25 mg/kg) and Hollis, B.W.; Singh, I.; Jenkins, D.D.
    [Show full text]
  • Delayed Dosing of Minocycline Plus N-Acetylcysteine Reduces Neurodegeneration in Distal Brain Regions and Restores Spatial Memor
    Manuscript bioRxiv preprint doi: https://doi.org/10.1101/2021.03.28.437090; this version posted March 29, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Delayed dosing of minocycline plus N-acetylcysteine reduces neurodegeneration in distal brain regions and restores spatial memory after experimental traumatic brain injury Kristen Whitney 1,2, Elena Nikulina1, Syed N. Rahman1, Alisia Alexis1 and Peter J. Bergold1,2 1Department of Physiology and Pharmacology 2Program in Neural and Behavioral Science, School of Graduate Studies State University of New York-Downstate Health Sciences University, Brooklyn NY 11215 Corresponding Author: [email protected] Department of Physiology and Pharmacology, Box 29 State University of New York – Downstate Health Sciences University 450 Clarkson Avenue Brooklyn, NY 11215 Declarations of interest: none Abbreviations: CHI- closed head injury Contra- contralateral Ipsi- ipsilateral MAP2 -microtubule associated protein 2 MINO- minocycline MN12- MINO plus NAC first dosed 12 hours after injury MN72- MINO plus NAC first dosed 72 hours after injury NAC- N-acetylcysteine TBI- Traumatic brain injury 1 bioRxiv preprint doi: https://doi.org/10.1101/2021.03.28.437090; this version posted March 29, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract Multiple drugs to treat traumatic brain injury (TBI) have failed clinical trials. Most drugs lose efficacy as the time interval increases between injury and treatment onset. Insufficient therapeutic time window is a major reason underlying failure in clinical trials.
    [Show full text]
  • Sulfhydryl Reduction of Methylene Blue with Reference to Alterations in Malignant Neoplastic Disease
    Sulfhydryl Reduction of Methylene Blue With Reference to Alterations in Malignant Neoplastic Disease Maurice M. Black, M. D. (From the Department of Biochemistry, New York Medical College, New York 29, N. t;., and the Brooklyn Cancer Institute, Brooklyn 9, N. Y.) (Received for publication May 8, 1947) A significant decrease in methylene blue re- reactivity is less than half that of the cysteine. It is ducing power of plasma from patients with malig- noteworthy also that the resultant leuco mixture nant neoplastic disease was previously reported did not revert back to colored methylene blue on (1). At that time it was suggested that change in a cooling, as was the case with methylene blue re- reducing group of the albumin molecule was a duction by plasma. likely source of this alteration. Similar conclusions Similar relationships were investigated between were reported also by Savignac and associates (7) cysteine and different concentrations of methylene as the result of analogous studies. blue. As seen in Fig. 2, similar curves are obtained, In an attempt to evaluate the effect of the sulf- but the position of the curve on the graph varies hydryl group on the reduction of methylene blue, a with the concentration of the methylene blue used. study was undertaken with various compounds of It should be noted that there is no appreciable known -SH and S-S structures. In addition, an difference in the reducing time of methylene blue attempt was made to establish a standard method on varying the concentrations between 0.10 per of calibration of various lots of methylene blue, so cent and 0.2 per cent, although 0.08 per cent shows that more uniform results would be possible in the a decided difference.
    [Show full text]
  • A Review of Dietary (Phyto)Nutrients for Glutathione Support
    nutrients Review A Review of Dietary (Phyto)Nutrients for Glutathione Support Deanna M. Minich 1,* and Benjamin I. Brown 2 1 Human Nutrition and Functional Medicine Graduate Program, University of Western States, 2900 NE 132nd Ave, Portland, OR 97230, USA 2 BCNH College of Nutrition and Health, 116–118 Finchley Road, London NW3 5HT, UK * Correspondence: [email protected] Received: 8 July 2019; Accepted: 23 August 2019; Published: 3 September 2019 Abstract: Glutathione is a tripeptide that plays a pivotal role in critical physiological processes resulting in effects relevant to diverse disease pathophysiology such as maintenance of redox balance, reduction of oxidative stress, enhancement of metabolic detoxification, and regulation of immune system function. The diverse roles of glutathione in physiology are relevant to a considerable body of evidence suggesting that glutathione status may be an important biomarker and treatment target in various chronic, age-related diseases. Yet, proper personalized balance in the individual is key as well as a better understanding of antioxidants and redox balance. Optimizing glutathione levels has been proposed as a strategy for health promotion and disease prevention, although clear, causal relationships between glutathione status and disease risk or treatment remain to be clarified. Nonetheless, human clinical research suggests that nutritional interventions, including amino acids, vitamins, minerals, phytochemicals, and foods can have important effects on circulating glutathione which may translate to clinical benefit. Importantly, genetic variation is a modifier of glutathione status and influences response to nutritional factors that impact glutathione levels. This narrative review explores clinical evidence for nutritional strategies that could be used to improve glutathione status.
    [Show full text]
  • Muscle Wasting and Aging: Experimental Models, Fatty Infiltrations, and Prevention Thomas Brioche, Allan Pagano, Guillaume Py, Angèle Chopard
    Muscle wasting and aging: Experimental models, fatty infiltrations, and prevention Thomas Brioche, Allan Pagano, Guillaume Py, Angèle Chopard To cite this version: Thomas Brioche, Allan Pagano, Guillaume Py, Angèle Chopard. Muscle wasting and aging: Experi- mental models, fatty infiltrations, and prevention. Molecular Aspects of Medicine, Elsevier, 2016,32 p. 10.1016/j.mam.2016.04.006. hal-01837630 HAL Id: hal-01837630 https://hal.archives-ouvertes.fr/hal-01837630 Submitted on 28 May 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Distributed under a Creative Commons Attribution - ShareAlike| 4.0 International License Accepted Manuscript Title: Muscle wasting and aging: experimental models, fatty infiltrations, and prevention Author: Thomas Brioche, Allan F. Pagano, Guillaume Py, Angèle Chopard PII: S0098-2997(15)30021-2 DOI: http://dx.doi.org/doi: 10.1016/j.mam.2016.04.006 Reference: JMAM 642 To appear in: Molecular Aspects of Medicine Received date: 19-12-2015 Revised date: 13-4-2016 Accepted date: 13-4-2016 Please cite this article as: Thomas Brioche, Allan F. Pagano, Guillaume Py, Angèle Chopard, Muscle wasting and aging: experimental models, fatty infiltrations, and prevention, Molecular Aspects of Medicine (2016), http://dx.doi.org/doi: 10.1016/j.mam.2016.04.006.
    [Show full text]
  • Minocycline Synergizes with N-Acetylcysteine and Improves Cognition and Memory Following Traumatic Brain Injury in Rats
    Minocycline Synergizes with N-Acetylcysteine and Improves Cognition and Memory Following Traumatic Brain Injury in Rats Samah G. Abdel Baki, Ben Schwab, Margalit Haber, Andre´ A. Fenton, Peter J. Bergold* Departments of Physiology and Pharmacology, State University of New York-Downstate Medical Center, Brooklyn, New York, United States of America Abstract Background: There are no drugs presently available to treat traumatic brain injury (TBI). A variety of single drugs have failed clinical trials suggesting a role for drug combinations. Drug combinations acting synergistically often provide the greatest combination of potency and safety. The drugs examined (minocycline (MINO), N-acetylcysteine (NAC), simvastatin, cyclosporine A, and progesterone) had FDA-approval for uses other than TBI and limited brain injury in experimental TBI models. Methodology/Principal Findings: Drugs were dosed one hour after injury using the controlled cortical impact (CCI) TBI model in adult rats. One week later, drugs were tested for efficacy and drug combinations tested for synergy on a hierarchy of behavioral tests that included active place avoidance testing. As monotherapy, only MINO improved acquisition of the massed version of active place avoidance that required memory lasting less than two hours. MINO-treated animals, however, were impaired during the spaced version of the same avoidance task that required 24-hour memory retention. Co- administration of NAC with MINO synergistically improved spaced learning. Examination of brain histology 2 weeks after injury suggested that MINO plus NAC preserved white, but not grey matter, since lesion volume was unaffected, yet myelin loss was attenuated. When dosed 3 hours before injury, MINO plus NAC as single drugs had no effect on interleukin-1 formation; together they synergistically lowered interleukin-1 levels.
    [Show full text]