NADH:Cytochrome b5 Reductase and Cytochrome b5 Can Act as Sole Electron Donors to Human Cytochrome P450 1A1-Mediated Oxidation and DNA Adduct Formation by Benzo[a]pyrene

Stiborová, Marie; Indra, Radek; Moserová, Michaela; Frei, Eva; Schmeiser, Heinz H.; Kopka, Klaus; Philips, David H.; Arlt, Volker M.

doi:10.1021/acs.chemrestox.6b00143

Cited by 32 publications

(51 citation statements)

References 56 publications

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“…Recently, we have found that the NADH:cytochrome b 5 reductase/cytochrome b 5 /NADH system can also substitute the POR/NADPH system and act as an electron donor to another CYP enzyme, CYP1A1, for the oxidation of benzo[ a ]pyrene (BaP). This NADH-dependent system can, therefore, function as a sole electron donor for both reduction steps in the reaction cycles of CYP1A1 [ 39 , 40 ] and CYP3A4 [ 26 , 28 ]. Here, we investigated in detail, whether the NADH:cytochrome b 5 reductase/cytochrome b 5 /NADH system can also be the sole electron donor in the CYP3A4-catalyzed oxidation of ellipticine, Another aim of this work was to shed more light on the further functions of cytochrome b 5 in this CYP3A4-mediated reaction.…”

Section: Introductionmentioning

confidence: 99%

Cytochrome b 5 plays a dual role in the reaction cycle of cytochrome P450 3A4 during oxidation of the anticancer drug ellipticine

et al. 2017

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Ellipticine is an anticancer agent that forms covalent DNA adducts after enzymatic activation by cytochrome P450 (CYP) enzymes, mainly by CYP3A4. This process is one of the most important ellipticine DNA-damaging mechanisms for its antitumor action. Here, we investigated the efficiencies of human hepatic microsomes and human recombinant CYP3A4 expressed with its reductase, NADPH:CYP oxidoreductase (POR), NADH:cytochrome b 5 reductase and/or cytochrome b 5 in Supersomes™ to oxidize this drug. We also evaluated the effectiveness of coenzymes of two of the microsomal reductases, NADPH as a coenzyme of POR, and NADH as a coenzyme of NADH:cytochrome b 5 reductase, to mediate ellipticine oxidation in these enzyme systems. Using HPLC analysis we detected up to five ellipticine metabolites, which were formed by human hepatic microsomes and human CYP3A4 in the presence of NADPH or NADH. Among ellipticine metabolites, 9-hydroxy-, 12-hydroxy-, and 13-hydroxyellipticine were formed by hepatic microsomes as the major metabolites, while 7-hydroxyellipticine and the ellipticine N 2-oxide were the minor ones. Human CYP3A4 in Supersomes™ generated only three metabolic products, 9-hydroxy-, 12-hydroxy-, and 13-hydroxyellipticine. Using the 32P-postlabeling method two ellipticine-derived DNA adducts were generated by microsomes and the CYP3A4-Supersome system, both in the presence of NADPH and NADH. These adducts were derived from the reaction of 13-hydroxy- and 12-hydroxyellipticine with deoxyguanosine in DNA. In the presence of NADPH or NADH, cytochrome b 5 stimulated the CYP3A4-mediated oxidation of ellipticine, but the stimulation effect differed for individual ellipticine metabolites. This heme protein also stimulated the formation of both ellipticine-DNA adducts. The results demonstrate that cytochrome b 5 plays a dual role in the CYP3A4-catalyzed oxidation of ellipticine: (1) cytochrome b 5 mediates CYP3A4 catalytic activities by donating the first and second electron to this enzyme in its catalytic cycle, indicating that NADH:cytochrome b 5 reductase can substitute NADPH-dependent POR in this enzymatic reaction and (2) cytochrome b 5 can act as an allosteric modifier of the CYP3A4 oxygenase.Graphical abstract

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Section: Introductionmentioning

confidence: 99%

Cytochrome b 5 plays a dual role in the reaction cycle of cytochrome P450 3A4 during oxidation of the anticancer drug ellipticine

et al. 2017

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“…The optimum conditions obtained were pH 4.5, contact time of 20 h, and at concentration of 50 mg/mL, with the adsorption capacity of 85 mg/1x10 6 T. viride colonies. The proposed mechanism for biosorption is through adsorption of Pb(II) ions in the cell walls of T. viride, involving negatively charged functional groups in T. viride such as COO  , -, dan -NH  , and positive charged from metal ions.…”

Section: Resultsmentioning

confidence: 98%

“…It can be used efficiently for the treatment of large volumes of waste with low concentrations of pollutants. Thus, the process does not depend on the viability of biomass [6]. The application of microorganisms as biosorbents has several advantages due to their small size and the ability to adsorption, binding the concentrations of heavy metals from aqueous solutions including very dilute concentrations by certain types of inactive, dead and living microbes [7].…”

Section: Introductionmentioning

confidence: 99%

Biosorption of Pb2+ using Trichoderma viride as Alternative Solution for Heavy Metal Pollution in the Waters

Taloin¹,

Safitri

Prasetyawan

et al. 2018

J. Pure App. Chem. Res.

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Lead is considered as one of water pollutant that is toxic, corrosive, and irritant. One method that can be applied for reducing Pb(II) in the environment is by using microorganisms. In this work, the study of biosorption of lead in the water samples was conducted using Trichoderma viride. The research was focused on the determination of optimum conditions of biosorption including initial pH, biosorption time, and initial concentration of lead. Profiles of functional groups contained in the T. viride have been monitored using FT-IR spectrophotometry. Results showed that the maximum biosorption of Pb(II) was achieved at initial pH 4.5, with equilibrium of contact time at 20 h, and optimum concentration of 50 mg/L, and adsorption capacity of 85 mg/1x10 6 T. viride colonies. The FTIR results indicated that biosorption process affected the functional groups in the T. viride. These have shown in the absorption bands at ~3200 cm -1 , ~2850 cm -1 , ~2260 cm -1 , ~1650 cm -1 , ~1450 cm -1 , 1180 cm -1 , and in the finger printing regions. The biosorption mechanism was proposed through the adsorption process between positively charged metal ions and the negative charge on the functional groups, such as COO  , OPO 3 2, and -NH 2  , on the cell surface.

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“…Free radicals participate a vital function in tumor initiation by modification of cellular metabolic processes or direct chemical reaction. The stimulation of carcinogen is mainly catalyzed by phase I (CYP 450 and Cyt‐b 5 ) enzymes and detoxified by the presence of phase II (GST and GR) enzymes thereby protecting against carcinogenic injury . The scavengers of phase II enzymes represent of inhibitors at all stages of carcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

Zingerone induced caspase‐dependent apoptosis in MCF‐7 cells and prevents 7,12‐dimethylbenz(a)anthracene‐induced mammary carcinogenesis in experimental rats

Gan

Zhang

Zhou

et al. 2019

J Biochem & Molecular Tox

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Breast cancer is a prevalent of tumoregenesis in women and reports for the maximum mortality and morbidity in the global. Ginger (Zingiber officinale) is the mainly widespread spice and herbal remedies used in the world. Since antique periods, ginger has been used in Greece, India and China for the curing of upset stomach, nausea, diarrhea, colds, and headaches. The current work was planned to explore the anticancer properties of zingerone (ZO) toward 7,12‐dimethylbenz(a)anthracene (DMBA)‐treated mammary carcinogenesis in Sprague‐Dawley (SD) rats and MCF‐7 mammary cancer cells. The mammary carcinogenesis was produced through a single dosage of DMBA (20 mg/kg bwt) mixed in soya oil (1 mL) administrated intragastrically with a gavage. We found improved concentrations of lipid peroxidation (LOOH and TBARS), carcinoembryonic antigen, lowered levels of enzymatic (CAT, GPx, and SOD), and nonenzymatic (vitamin E, GSH, and vitamin C) antioxidant in mammary tissues and plasma of DMBA‐induced cancer bearing animals. Moreover, augmented concentrations of phase I (Cyt‐b5 and CYP450) and reduced levels of phase II (GR and GST) detoxification microsomal proteins in mammary tissues were noticed. ZO administrations significantly reverted back to all these parameters in this way, showing efficient of anticancer effect. Furthermore, our in vitro study also supported the anticancer effect of the treatment of ZO were noticed loss of cell viability, improved reactive oxygen species formation, and reduced MMP. Furthermore, the status of apoptosis proteins such as Bcl‐2, Bax, and Bid expressions was determined by using Western blot analysis techniques. Overall, these results proposed the anticancer effect of ZO toward DMBA‐induced mammary cancer in SD animals and Michigan cancer foundation‐7 mammary cancer cells.

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NADH:Cytochrome b₅ Reductase and Cytochrome b₅ Can Act as Sole Electron Donors to Human Cytochrome P450 1A1-Mediated Oxidation and DNA Adduct Formation by Benzo[a]pyrene

Cited by 32 publications

References 56 publications

Cytochrome b 5 plays a dual role in the reaction cycle of cytochrome P450 3A4 during oxidation of the anticancer drug ellipticine

Cytochrome b 5 plays a dual role in the reaction cycle of cytochrome P450 3A4 during oxidation of the anticancer drug ellipticine

Biosorption of Pb2+ using Trichoderma viride as Alternative Solution for Heavy Metal Pollution in the Waters

Zingerone induced caspase‐dependent apoptosis in MCF‐7 cells and prevents 7,12‐dimethylbenz(a)anthracene‐induced mammary carcinogenesis in experimental rats

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