DNA Damage in AML-12 Hepatocytes and 3T3-L1 Adipocytes Treated with Clopidogrel

Background: Clopidogrel has been commonly prescribed as a selective P2Y12 receptor antagonist to reduce heart attack and stroke risk. Nearly 10 % of absorbed clopidogrel is metabolized by cytochrome P450 (CYP) enzymes in the liver to active forms and 90 % to inactive clopidogrel carboxylate by esterases. Objective: Since different forms of clopidogrel have cytotoxic potential, our aim was to determinate the effect of clopidogrel (7.5, 40 and 75µM) over DNA damage in adipocyte and hepatocytes. Material Methods: In the present study DNA damage was investigated by Comet analysis using 3T3-L1 adipocytes and Alpha Mouse 12 (AML-12) hepatocytes. Results: DNA fragmentation was found to be increased as a response to 7.5 µM, 40 µM and 75 µM clopidogrel treatment compared to non-treated control groups in AML-12 hepatocytes (p<0.01, p<0.001, p<0.01 respectively) and 3T3-L1 adipocytes (p<0.001, p<0.001 and p<0.001 respectively). DNA damage levels as a response to clopidogrel treatment was found to be higher in 3T3-L1 adipocytes than AML-12 hepatocytes. Also, DNA damage levels in adipocytes and hepatocytes were found to increase dose dependently for 7.5 and 40 μM clopidogrel whereas decreased as a response to 75 μM. Conclusion: According to our results, clopidogrel results in more DNA damage in adipocytes than in hepatocytes. The molecular mechanism of clopidogrel genotoxicity need to be further investigated especially in adipose tissue.

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Faculty Opinions recommendation of A molecular mechanism for DNA damage recognition by the xeroderma pigmentosum group C protein complex.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1011200.178317 ◽

2003 ◽

Author(s):

Errol C Friedberg

Keyword(s):

Dna Damage ◽

Molecular Mechanism ◽

Protein Complex ◽

Xeroderma Pigmentosum ◽

C Protein ◽

Damage Recognition ◽

Dna Damage Recognition

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Metal-mediated DNA damage induced by curcumin in the presence of human cytochrome P450 isozymes

Archives of Biochemistry and Biophysics ◽

10.1016/s0003-9861(02)00302-8 ◽

2002 ◽

Vol 405 (2) ◽

pp. 223-230 ◽

Cited By ~ 36

Author(s):

Katsuhisa Sakano ◽

Shosuke Kawanishi

Keyword(s):

Dna Damage ◽

Cytochrome P450 ◽

Human Cytochrome ◽

P450 Isozymes ◽

Cytochrome P450 Isozymes

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The Anticancer Drug Ellipticine Activated with Cytochrome P450 Mediates DNA Damage Determining Its Pharmacological Efficiencies: Studies with Rats, Hepatic Cytochrome P450 Reductase Null (HRN™) Mice and Pure Enzymes

International Journal of Molecular Sciences ◽

10.3390/ijms16010284 ◽

2014 ◽

Vol 16 (1) ◽

pp. 284-306 ◽

Cited By ~ 14

Author(s):

Marie Stiborová ◽

Věra Černá ◽

Michaela Moserová ◽

Iveta Mrízová ◽

Volker Arlt ◽

...

Keyword(s):

Dna Damage ◽

Cytochrome P450 ◽

Anticancer Drug ◽

Cytochrome P450 Reductase ◽

P450 Reductase ◽

Hepatic Cytochrome

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Evaluation of the Protective Effects of Quercetin, Rutin, Naringenin, Resveratrol and Trolox Against Idarubicin-Induced DNA Damage

Journal of Pharmacy & Pharmaceutical Sciences ◽

10.18433/j3s01g ◽

2010 ◽

Vol 13 (2) ◽

pp. 231 ◽

Cited By ~ 25

Author(s):

Haydar Çelik ◽

Emel Arinç

Keyword(s):

Dna Damage ◽

Cytochrome P450 ◽

Mitomycin C ◽

Dna Strand Breaks ◽

Protective Effects ◽

Cytochrome P450 Reductase ◽

Strand Breaks ◽

P450 Reductase ◽

Nadph Cytochrome P450 Reductase ◽

Dna Strand

PURPOSE. Idarubicin is a synthetic anthracycline anticancer drug widely used in the treatment of some hematological malignancies. The studies in our laboratory have clearly demonstrated that idarubicin can undergo reductive bioactivation by NADPH-cytochrome P450 reductase to free radicals with resulting formation of DNA strand breaks, which can potentially contribute to its genotoxic effects [Çelik, H., Arinç, E., Bioreduction of idarubicin and formation of ROS responsible for DNA cleavage by NADPH-cytochrome P450 reductase and its potential role in the antitumor effect. J Pharm Pharm Sci, 11(4):68-82, 2008]. In the current study, our aim was to investigate the possible protective effects of several phenolic antioxidants, quercetin, rutin, naringenin, resveratrol and trolox, against the DNA-damaging effect of idarubicin originating from its P450 reductase-catalyzed bioactivation. METHODS. DNA damage was measured by detecting single-strand breaks in plasmid pBR322 DNA using a cell-free agarose gel method. RESULTS. Our results indicated that, among the compounds tested, quercetin was the most potent antioxidant in preventing DNA damage. Quercetin significantly decreased the extent of DNA strand breaks in a dose-dependent manner; 100 μM of quercetin almost completely inhibited the DNA strand breakage. Unlike quercetin, its glycosidated conjugate rutin, failed to provide any significant protection against idarubicin-induced DNA strand breaks except at the highest concentration tested (2 mM). The protective effects of other antioxidants were significantly less than that of quercetin even at high concentrations. Quercetin was found to be also an effective protector against DNA damage induced by mitomycin C. CONCLUSION. We conclude that quercetin, one of the most abundant flavonoids in the human diet, is highly effective in reducing the DNA damage caused by the antitumor agents, idarubicin and mitomycin C, following bioactivation by P450 reductase.

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Identification of Human Liver Cytochrome P450 Enzymes Involved in Biotransformation of Vicriviroc, a CCR5 Receptor Antagonist

Drug Metabolism and Disposition ◽

10.1124/dmd.107.017517 ◽

2007 ◽

Vol 35 (12) ◽

pp. 2186-2195 ◽

Cited By ~ 22

Author(s):

Anima Ghosal ◽

Ragu Ramanathan ◽

Yuan Yuan ◽

Neil Hapangama ◽

Swapan K. Chowdhury ◽

...

Keyword(s):

Cytochrome P450 ◽

Receptor Antagonist ◽

Human Liver ◽

Cytochrome P450 Enzymes ◽

Liver Cytochrome ◽

Ccr5 Receptor

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Ruthenium-containing P450 inhibitors for dual enzyme inhibition and DNA damage

Dalton Transactions ◽

10.1039/c6dt04405k ◽

2017 ◽

Vol 46 (7) ◽

pp. 2165-2173 ◽

Cited By ~ 32

Author(s):

Ana Zamora ◽

Catherine A. Denning ◽

David K. Heidary ◽

Erin Wachter ◽

Leona A. Nease ◽

...

Keyword(s):

Dna Damage ◽

Drug Resistance ◽

Cytochrome P450 ◽

Enzyme Inhibition ◽

Metal Center ◽

P450 Inhibitors

A light-activated prodrug delivers both a DNA damaging metal center and a cytochrome P450 inhibitor to prevent drug resistance.

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The Mineralocorticoid Receptor Antagonist Eplerenone Suppress Interstitial Fibrosis in Subcutaneous Adipose Tissue in Type 2 Diabetes Patients

10.2337/figshare.13050743.v1 ◽

2020 ◽

Author(s):

Ada Admin ◽

Marie Louise Johansen ◽

Jaime Ibarrola ◽

Amaya Fernández-Celis ◽

Morten Schou ◽

...

Keyword(s):

Type 2 Diabetes ◽

Adipose Tissue ◽

Receptor Antagonist ◽

Subcutaneous Adipose Tissue ◽

Mineralocorticoid Receptor ◽

Prostaglandin D2 ◽

Type I ◽

Mineralocorticoid Receptor Antagonist ◽

Subcutaneous Adipose

Activation of the mineralocorticoid receptor (MR) may promote dysfunctional adipose tissue in patients with type 2 diabetes, where increased pericellular fibrosis has emerged as a major contributor. The knowledge of the association between the MR, fibrosis and the effects of an MR antagonist (MRA) in human adipocytes remains very limited. The present sub-study including 30 participants was prespecified as part of the Mineralocorticoid Receptor Antagonist in type 2 Diabetes (MIRAD) trial, randomizing patients to either high dose eplerenone or placebo for 26 weeks. In adipose tissue biopsies, changes in fibrosis were evaluated by immunohistological examinations and by the expression of mRNA and protein markers of fibrosis. Treatment with an MRA reduced pericellular fibrosis, synthesis of the major subunits of collagen type I and VI, and the profibrotic factor α-smooth muscle actin, as compared to placebo in subcutaneous adipose tissue. Furthermore, we found decreased expression of the MR and downstream molecules neutrophil gelatinase–associated lipocalin, galectin-3, and lipocalin-like prostaglandin D2 synthase with an MRA. In conclusions, we present original data demonstrating reduced fibrosis in adipose tissue with inhibition of the MR, which could be a potential therapeutic approach to prevent the extracellular matrix remodeling of adipose tissue in type 2 diabetes.

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