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Diclofenac Induced In Vivo Nephrotoxicity May Involve Oxidative Stress-mediated Massive Genomic DNA Fragmentation And Apoptotic Cell Death.
E. Hickey, R. Raje, V. Reid, S. Gross, S. Ray
Published 2001 · Chemistry, Medicine
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Diclofenac (DCLF) is a nonsteroidal anti-inflammatory drug that is widely used for the treatment of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, and acute muscle pain conditions. Toxic doses of DCLF can cause nephrotoxicity in humans and experimental animals. However, whether this DCLF-induced nephrotoxicity involves apoptotic cell death in addition to necrosis is unknown. The goals of this investigation were to determine whether DCLF-induced nephrotoxicity involves oxidative stress and apoptotic type genomic DNA fragmentation, and if so, whether DCLF-induced oxidative stress and DNA fragmentation cause apoptotic cell death in mouse kidneys. Male ICR mice (CD-1; 25-45 g), fed ad libitum, were administered nephrotoxic doses of DCLF (100, 200, 300 mg/Kg, po) and sacrificed 24 h later. Blood was collected to evaluate renal injury (BUN), lipid peroxidation (MDA: malondialdehyde levels), and superoxide dismutase (SOD) activity (a marker of oxidative stress). Kidney tissues were analyzed both quantitatively and qualitatively to determine the degree and type of DNA damage, and evaluated histopathologically for the presence of apoptotic characteristics in the nucleus of diverse types of kidney cells. Results show that diclofenac is a powerful nephrotoxicant (at 100, 200, and 300 mg/kg: 4.7-, 4.9-, and 5.0-fold increases in BUN compared to the control, respectively) and a strong inducer of oxidative stress (significant increase in MDA levels). Oxidative stress induced by DCLF was also coupled with massive kidney DNA fragmentation (100, 200, and 300 mg/kg: 3-, 8-, and 10-fold increases compared to control, respectively). A dose-dependent increase in MDA levels and SOD activity was also observed, which indicated a link between oxidative stress and nephrotoxicity. Qualitative analysis of DNA fragmentation by gel electrophoresis showed a DNA ladder indicative of Ca2+-Mg2+-endonuclease activation. Histopathological examination of kidney sections revealed numerous apoptotic nuclei across proximal and distal tubular cell linings. Collectively, these data for the first time suggest that DCLF-induced nephrotoxicity may involve production of reactive oxygen species leading to oxidative stress and massive genomic DNA fragmentation, and these two free radical mediated events may ultimately translate into apoptotic cell death of kidney cells in vivo, and reveal a DNA-active role for DCLF.
This paper references
A study of the conditions and mechanism of the diphenylamine reaction for the colorimetric estimation of deoxyribonucleic acid.
K. Burton (1956)
[ENZYMATIC UREA DETERMINATION IN THE BLOOD AND SERUM IN THE WARBURG OPTICAL TEST].
H. Talke (1965)
Diclofenac-associated acute renal failure. Report of 2 cases.
E. Rossi (1985)
Pentoxifylline. A review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic efficacy.
A. Ward (1987)
Ca2+ release from mitochondria induced by prooxidants.
C. Richter (1988)
The biochemistry of cell death by apoptosis.
W. Bursch (1990)
Modulation of fibroblast proliferation by oxygen free radicals
G. C. Murrell (1990)
Early loss of large genomic DNA in vivo with accumulation of Ca2+ in the nucleus during acetaminophen-induced liver injury.
S. Ray (1990)
Phosphate, not superoxide dismutase, facilitates electron transfer from ferrous salts to cytochrome c.
W. Beyer (1991)
Noncyclooxygenase metabolites of arachidonic acid amplify the vasopressin-induced Ca2+ signal in glomerular mesangial cells by releasing Ca2+ from intracellular stores.
T. Force (1991)
Extensive alteration of genomic DNA and rise in nuclear Ca2+ in vivo early after hepatotoxic acetaminophen overdose in mice.
S. Ray (1991)
Cancer destruction in vivo through disrupted energy metabolism. Part I. The endogenous mechanism of self-destruction within the malignant cell, and the roles of endotoxin, certain hormones and drugs, and active oxygen in causing cellular injury and death.
G. Jones (1992)
Ca(++)-activated DNA fragmentation and dimethylnitrosamine-induced hepatic necrosis: effects of Ca(++)-endonuclease and poly(ADP-ribose) polymerase inhibitors in mice.
S. Ray (1992)
Cancer destruction in vivo through disrupted energy metabolism. Part III. Spontaneous drug resistance, selectivity of antineoplastic action, and strategies for intensifying tumor injury.
G. Jones (1992)
Role of intracellular calcium in hydrogen peroxide-induced renal tubular cell injury.
N. Ueda (1992)
Protective effects of antioxidants against endrin-induced hepatic lipid peroxidation, DNA damage, and excretion of urinary lipid metabolites.
D. Bagchi (1993)
Apoptosis: the biochemistry and molecular biology of programmed cell death.
R. A. Schwartzman (1993)
Spectrophotometric assay of superoxide dismutase activity based on the activated autoxidation of a tetracyclic catechol.
C. Nebot (1993)
Relationship between mitochondrial superoxide and hydrogen peroxide production and longevity of mammalian species.
H. Ku (1993)
Ca2+ antagonists inhibit DNA fragmentation and toxic cell death induced by acetaminophen 1
S. Ray (1993)
Metabolic activation and immunochemical localization of liver protein adducts of the nonsteroidal anti-inflammatory drug diclofenac.
S. Hargus (1994)
INVITED COMMENTARY IS APOPTOSIS MEDIATED BY REACTIVE OXYGEN SPECIES
T. Sarafian (1994)
Differential inhibition of human prostaglandin endoperoxide H synthases-1 and -2 by nonsteroidal anti-inflammatory drugs.
O. Laneuville (1994)
Oxidative stress-induced apoptosis prevented by Trolox.
V. Forrest (1994)
Role of cellular energy status in tocopheryl hemisuccinate cytoprotection against ethyl methanesulfonate-induced toxicity.
S. Ray (1994)
Oxidative stress as a mediator of apoptosis.
T. Buttke (1994)
Calcium-mediated cell injury and cell death.
B. Trump (1995)
Expression and selective inhibition of the constitutive and inducible forms of human cyclo-oxygenase.
J. Gierse (1995)
Differential effect of Ca2+ on oxidant-induced lethal cell injury and alterations of membrane functional integrity in renal cortical slices.
Y. Kim (1996)
Lipid peroxidation contributes to hydrogen peroxide induced cytotoxicity in renal epithelial cells.
A. M. Sheridan (1996)
Protection of acetaminophen-induced hepatocellular apoptosis and necrosis by cholesteryl hemisuccinate pretreatment.
S. Ray (1996)
Catalase and superoxide dismutase activities as biomarkers of oxidative stress in workers exposed to mercury vapors.
R. Perrin-Nadif (1996)
In vitro interaction of nonsteroidal anti-inflammatory drugs on oxidative phosphorylation of rat kidney mitochondria: respiration and ATP synthesis.
F. E. Mingatto (1996)
Cytochrome P4502C11 is a target of diclofenac covalent binding in rats.
S. Shen (1997)
Urinary gamma-glutamyl transferase activity in rats with nonsteroidal anti-inflammatory drug-induced nephrotoxicity.
S. Kocaoğlu (1997)
Diclofenac sodium and mefenamic acid: potent inducers of the membrane permeability transition in renal cortex mitochondria.
S. A. Uyemura (1997)
Activation of NF‐κB protects hippocampal neurons against oxidative stress‐induced apoptosis: Evidence for induction of manganese superoxide dismutase and suppression of peroxynitrite production and protein tyrosine nitration
Mark P. Mattson (1997)
Uncoupling effects of diclofenac and aspirin in the perfused liver and isolated hepatic mitochondria of rat.
I. Petrescu (1997)
Oxidation of diclofenac to reactive intermediates by neutrophils, myeloperoxidase, and hypochlorous acid.
G. Miyamoto (1997)
DFF, a Heterodimeric Protein That Functions Downstream of Caspase-3 to Trigger DNA Fragmentation during Apoptosis
X. Liu (1997)
Influence of nonsteroidal anti-inflammatory drugs on calcium efflux in isolated rat renal cortex mitochondria and aspects of the mechanisms involved.
A. A. Pigoso (1998)
Alterations of antioxidant enzyme expression in response to hydrogen peroxide.
E. Roehrdanz (1998)
The Bcl-2 protein family: arbiters of cell survival.
J. Adams (1998)
A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD
M. Enari (1998)
Inhibition and uncoupling of oxidative phosphorylation by nonsteroidal anti-inflammatory drugs: study in mitochondria, submitochondrial particles, cells, and whole heart.
R. Moreno-Sánchez (1999)
Roles of human hepatic cytochrome P450s 2C9 and 3A4 in the metabolic activation of diclofenac.
W. Tang (1999)
Studies on cytochrome P-450-mediated bioactivation of diclofenac in rats and in human hepatocytes: identification of glutathione conjugated metabolites.
W. Tang (1999)
Smokeless tobacco, oxidative stress, apoptosis, and antioxidants in human oral keratinocytes.
M. Bagchi (1999)
Free radical-induced megamitochondria formation and apoptosis.
M. Karbowski (1999)
Metabolic activation of diclofenac by human cytochrome P450 3A4: role of 5-hydroxydiclofenac.
S. Shen (1999)
Renal dysfunction associated with the perioperative use of diclofenac.
H. Kim (1999)
Diclofenac toxicity to hepatocytes: a role for drug metabolism in cell toxicity.
R. Bort (1999)
A novel proanthocyanidin IH636 grape seed extract increases in vivo Bcl-XL expression and prevents acetaminophen-induced programmed and unprogrammed cell death in mouse liver.
S. Ray (1999)
Polynucleotide degradation during early stage response to oxidative stress is specific to mitochondria.
N. E. Abramova (2000)
Oxidants, oxidative stress and the biology of ageing
T. Finkel (2000)
Progressive left ventricular remodeling and apoptosis late after myocardial infarction in mouse heart.
F. Sam (2000)
A hepatotoxic dose of acetaminophen modulates expression of BCL-2, BCL-XL, and BCL-XS during apoptotic and necrotic death of mouse liver cells in vivo
S. Ray (2000)
Age‐Related Changes in Irradiation‐Induced Apoptosis and Expression of p21 and p53 in Crypt Stem Cells of Murine Intestine
K. Martin (2000)
Corpse clearance defines the meaning of cell death
J. Savill (2000)
In vivo protection of dna damage associated apoptotic and necrotic cell deaths during acetaminophen-induced nephrotoxicity, amiodarone-induced lung toxicity and doxorubicin-induced cardiotoxicity by a novel IH636 grape seed proanthocyanidin extract.
S. Ray (2000)
The Bcl-2 protein family.
B. Antonsson (2000)
Apoptotic DNA fragmentation.
S. Nagata (2000)
Apoptosis during sexual differentiation of the bed nucleus of the stria terminalis in the rat brain.
W. Chung (2000)
Protection from lethal apoptosis in lipopolysaccharide-induced acute lung injury in mice by a caspase inhibitor.
M. Kawasaki (2000)
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Mathias Busch (2021)
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The possible oxidative stress and DNA damage induced in Diclofenac-exposed Non-target organisms in the aquatic environment: A systematic review
Seyyed Abbas Mirzaee (2021)
Diclofenac removal from wastewater by activated carbon
Effect of paraquat on cytotoxicity involved in oxidative stress and inflammatory reaction: A review of mechanisms and ecological implications.
Jiaxin Chen (2021)
Umbelliferone Inhibits Spermatogenic Defects and Testicular Injury in Lead-Intoxicated Rats by Suppressing Oxidative Stress and Inflammation, and Improving Nrf2/HO-1 Signaling
M. Alotaibi (2020)
Histopathological aspects of co-administration of dexamethasone and diclofenac sodium on male albino rats
A. Sharef (2020)
Gallic Acid Exerts Nephroprotective, Anti-Oxidative Stress, and Anti-Inflammatory Effects Against Diclofenac-Induced Renal Injury in Malerats.
A. Moradi (2020)
PHARMACOKINETICS OF CIPROFLOXACIN AND ITS INTERACTION WITH DICLOFENAC AFTER INTRAVENOUS INJECTION IN HEALTHY RABBITS
W. El-SheikhM. (2020)
Neuroprotective Effects of Chrysin on Diclofenac-Induced Apoptosis in SH-SY5Y Cells
E. Darendelioglu (2020)
Diclofenac-induced cytotoxicity in cultured carp leukocytes.
M. Němcová (2020)
Eucalyptus Globulus protects against diclofenac sodium induced hepatorenal and testicular toxicity in male rats
A. Mousa (2019)
Thymoquinone alleviates mitochondrial viability and apoptosis in diclofenac-induced acute kidney injury (AKI) via regulating Mfn2 and miR-34a mRNA expressions
K. Hashem (2020)
Fakhria Al-Joufi (2020)
Kolaviron Diminishes Diclofenac-Induced Liver and Kidney Toxicity in Wistar Rats Via Suppressing Inflammatory Events, Upregulating Antioxidant Defenses, and Improving Hematological Indices
Q. Alabi (2020)
The effects of different doses of diclofenac sodium on newborn rat hippocampus exposed during the third trimester
E. Elibol (2020)
Selenium attenuates diclofenac‐induced testicular and epididymal toxicity in rats
S. Owumi (2020)
Controlled and tuneable drug release from electrospun fibers and a non-invasive approach for cytotoxicity testing
G. Piccirillo (2019)
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Raouya Soussi (2019)
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