scholarly journals 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

2014 ◽  
Vol 16 (1) ◽  
pp. 284-306 ◽  
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

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

2010 ◽  
Vol 13 (2) ◽  
pp. 231 ◽  
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.

scholarly journals Improved hepatic physiology in hepatic cytochrome P450 reductase null (HRN™) mice dosed orally with fenclozic acid

2017 ◽  
Vol 6 (1) ◽  
pp. 81-88 ◽  
Author(s):  
James A. Akingbasote ◽  
Alison J. Foster ◽  
Huw B. Jones ◽  
Rhiannon David ◽  
Nigel J. Gooderham ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Drug Toxicity ◽  
Cytochrome P450 Reductase ◽  
Hepatic Drug ◽  
P450 Reductase ◽  
Liver Histopathology ◽  
Drug Biotransformation ◽  
Fenclozic Acid ◽  
Hepatic Cytochrome

HRN™ mice are valuable for P450-related hepatic drug biotransformation assessment, but not drug toxicity due to underlying liver histopathology.

Hepatic effects of repeated oral administration of diclofenac to hepatic cytochrome P450 reductase null (HRN™) and wild-type mice

2015 ◽  
Vol 90 (4) ◽  
pp. 853-862 ◽  
Author(s):  
James A. Akingbasote ◽  
Alison J. Foster ◽  
Ian Wilson ◽  
Sunil Sarda ◽  
Huw B. Jones ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Oral Administration ◽  
Cytochrome P450 Reductase ◽  
Wild Type ◽  
P450 Reductase ◽  
Hepatic Cytochrome

scholarly journals Molecular Docking Studies of ROS Agent from Quinone Family to Reductase Enzymes:Implication in Finding Anticancer Drug Candidate

2021 ◽  
Vol 14 (02) ◽  
pp. 681-689
Author(s):  
Hesti L. Wiraswati ◽  
Fida M. Warganegara ◽  
Akhmaloka Akhmaloka ◽  
Muhamad A. Martoprawiro
Keyword(s):  
Cytochrome P450 ◽  
Anticancer Drug ◽  
Molecular Interaction ◽  
Docking Studies ◽  
Cancer Drug ◽  
Drug Candidate ◽  
Cytochrome P450 Reductase ◽  
P450 Reductase ◽  
Quinone Reduction ◽  
Oxidoreductase Enzymes

Understanding the metabolism of cytotoxic compounds of quinone family is importance in cancer therapy because they have been successfully explored for their anti-tumor activity. Quinone which form radical semiquinone (by reductase enzymes) to generate Reactive Oxygen Species (ROS) is associated to be anticancer drug candidate. However, molecular mechanism of those compounds to reductase enzymes has not yet clearly understood.This study aimed to understand molecular interaction of quinones to oxidoreductase enzymes such as cytochrome P450 reductase or ubiquinone reductase (NQO1), or apoptosis inducing factor (AIF) which is recently reported as NADH:quinone reductase. In silico approach was applied to find the best affinity of each compound to enzymes. Optimize ligands were employed using Marvin sketch program. Molecular interaction using autodockvina software was built to measure important residues for quinone reduction. Docking analysis showed that generally quinones prefer bound to cytochrome P450 reductase rather than NQO1 or AIF. The number of ring seems affect to the affinity, but not for its functional groups. Residues analysis confirmed that reduction of quinone is NAD(P)H: dependent. The result revealedthat all ligands have high possibility to compete with their redox coupleswhich is needed in its capacity as an anti-cancer drug.

scholarly journals Relationship between hepatic phenotype and changes in gene expression in cytochrome P450 reductase (POR) null mice

2005 ◽  
Vol 388 (3) ◽  
pp. 857-867 ◽  
Author(s):  
Xiu Jun WANG ◽  
Mark CHAMBERLAIN ◽  
Olga VASSIEVA ◽  
Colin J. HENDERSON ◽  
C. Roland WOLF
Keyword(s):  
Cytochrome P450 ◽  
Bile Acid ◽  
Serum Testosterone ◽  
Cytochrome P450 Reductase ◽  
Endogenous Factors ◽  
Key Enzymes ◽  
P450 Reductase ◽  
Cytochrome P450 Activity ◽  
Steroid Dehydrogenase ◽  
Hepatic Cytochrome

Cytochrome P450 reductase is the unique electron donor for microsomal cytochrome P450s; these enzymes play a major role in the metabolism of endogenous and xenobiotic compounds. In mice with a liver-specific deletion of cytochrome P450 reductase, hepatic cytochrome P450 activity is ablated, with consequent changes in bile acid and lipid homoeostasis. In order to gain insights into the metabolic changes resulting from this phenotype, we have analysed changes in hepatic mRNA expression using microarray analysis and real-time PCR. In parallel with the perturbations in bile acid levels, changes in the expression of key enzymes involved in cholesterol and lipid homoeostasis were observed in hepatic cytochrome P450 reductase null mice. This was characterized by a reduced expression of Cyp7b1, and elevation of Cyp7a1 and Cyp8b1 expression. The levels of mRNAs for other cytochrome P450 genes, including Cyp2b10, Cyp2c29, Cyp3a11 and Cyp3a16, were increased, demonstrating that endogenous factors play a role in regulating the expression of these proteins and that the increases are due, at least in part, to altered levels of transcripts. In addition, levels of mRNAs encoding genes involved in glycolysis and lipid transport were also increased; the latter may provide an explanation for the increased hepatic lipid content observed in the hepatic null mice. Serum testosterone and oestradiol levels were lowered, accompanied by significantly decreased expression of Hsd3b2 (3β-hydroxy-Δ5-steroid dehydrogenase-2), Hsd3b5 (3β-hydroxy-Δ5-steroid dehydrogenase-5) and Hsd11b1 (11β-hydroxysteroid dehydrogenase type 1), key enzymes in steroid hormone metabolism. These microarray data provide important insights into the control of metabolic pathways by the cytochrome system.

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