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.

Fatty Liver and Impaired Hepatic Metabolism Alters the Congener-Specific Distribution of Polychlorinated Biphenyls (PCBs) in Mice with a Liver-Specific Deletion of Cytochrome P450 Reductase

2020 ◽  
Author(s):  
Xueshu Li ◽  
Chun-Yun Zhang ◽  
Hans-Joachim Lehmler
Keyword(s):  
Cytochrome P450 ◽  
Polychlorinated Biphenyls ◽  
Fatty Liver ◽  
Partition Coefficients ◽  
Hepatic Metabolism ◽  
Gas Chromatography Mass Spectrometry ◽  
Cytochrome P450 Reductase ◽  
P450 Reductase ◽  
Specific Distribution ◽  
Specific Deletion

Polychlorinated biphenyls (PCBs) are persistent organic pollutants that are linked to adverse health outcomes. PCB tissue levels are determinants of PCB toxicity; however, it is unclear how factors, such as an altered metabolism and/or a fatty liver, affect PCB distribution in vivo. We determined the congener-specific disposition of PCBs in mice with a liver specific deletion of cytochrome P450 reductase (KO), a model of fatty liver with impaired hepatic metabolism, and wildtype (WT) mice. Male and female KO and WT mice were exposed orally to Aroclor 1254, a technical PCB mixture. PCBs were quantified in adipose, blood, brain and liver tissues by gas chromatography-mass spectrometry. PCB profiles and levels in tissues were genotype and sex dependent. PCB levels were higher in the liver from KO compared to WT mice. PCB profiles showed clear differences between tissues from the same exposure group. While experimental tissue : blood partition coefficients in KO and WT mice did not follow the trends predicted using a composition-based model, the agreement between experimental and calculated partition coefficients was still reasonable. Thus, a fatty liver and/or an impaired hepatic metabolism alter the distribution of PCBs in mice and the magnitude of the partitioning of PCBs from blood into tissues can be approximated using composition-based models.<br>

scholarly journals KEMTUB012-NI2, a novel potent tubulysin analog that selectively targets hypoxic cancer cells and is potentiated by cytochrome p450 reductase downregulation

Hypoxia ◽  
2017 ◽  
Vol Volume 5 ◽  
pp. 45-59
Author(s):  
Paolo Lazzari ◽  
Marco Spiga ◽  
Monica Sani ◽  
Matteo Zanda ◽  
Ian N Fleming
Keyword(s):  
Cytochrome P450 ◽  
Cancer Cells ◽  
Cytochrome P450 Reductase ◽  
P450 Reductase

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.

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