By a News Reporter-Staff News Editor at Biotech Week -- Fresh data on Drugs and Therapies are presented in a new report. According to news reporting out of Amsterdam, Netherlands, by NewsRx editors, research stated, "NAD(P)H:quinone oxidoreductase 1 (NQO1) is an enzyme capable of reducing a broad range of chemically reactive quinones and quinoneimines (QIs) and can be strongly upregulated by Nrf2/Keap1-mediated stress responses. Several commonly used drugs implicated in adverse drug reactions (ADRs) are known to form reactive QI metabolites upon bioactivation by P450, such as acetaminophen (APAP), diclofenac (DF), and mefenamic acid (MFA)."
Our news journalists obtained a quote from the research from Vrije University, "In the present study, the reductive activity of human NQO1 toward the QI metabolites derived from APAP and hydroxy-metabolites of DF and MFA was studied, using purified bacterial P450 BM3 (CYP102A1) mutant M11 as a bioactivation system. The NQO1-catalyzed reduction of the QI metabolites was quantified relative to spontaneous glutathione (GSH) conjugation. Addition of NQO1 to the incubations strongly reduced the formation of all corresponding GSH conjugates, and this activity could be prevented by dicoumarol, a selective NQO1 inhibitor. The GSH conjugation was strongly increased by adding human GSTP1-1 in a wide range of GSH concentrations. Still, NQO1 could effectively compete with the GST catalyzed GSH conjugation by reducing the QIs."
According to the news editors, the research concluded: "We identified the QI metabolites of the 4'- and 5-hydroxy-metabolites of DF and MFA as novel substrates for human NQO1. NQO1-mediated reduction proves to be an effective pathway to detoxify these QI metabolites in addition to GSH conjugation. Genetically determined deficiency of NQO1 therefore might be a risk factor for ADRs induced by reactive QI drug metabolites."
For more information on this research see: Human NAD(P)H:quinone Oxidoreductase 1 (NQO1)-Mediated Inactivation of Reactive Quinoneimine Metabolites of Diclofenac and Mefenamic Acid. Chemical Research in Toxicology, 2014;27(4):576-586. Chemical Research in Toxicology can be contacted at: Amer Chemical Soc, 1155 16TH St, NW, Washington, DC 20036, USA. (American Chemical Society - www.acs.org; Chemical Research in Toxicology - www.pubs.acs.org/journal/crtoec)
Our news journalists report that additional information may be obtained by contacting G. Vredenburg, Vrije Universiteit Amsterdam, AIMMS, Div Mol Toxicol, Fac Sci, NL-1081 HV Amsterdam, Netherlands. Additional authors for this research include N.S. Elias, H. Venkataraman, D.F.G. Hendriks, N.P.E. Vermeulen, J.N.M. Commandeur and J.C. Vos (see also Drugs and Therapies).
Keywords for this news article include: NSAID, Europe, Amsterdam, Diclofenac, Netherlands, Phenylacetates, Topical Agents, Drugs and Therapies, Ophthalmic Preparations, Cyclooxygenase Inhibitors, Ophthalmic Antiinflammatory Agents
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