Low kinetic hydrogen isotope effects in the dehydrogenation of 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylic acid dimethyl ester (nifedipine) by cytochrome P-450 enzymes are consistent with an electron/proton/electron transfer mechan


:Cytochrome P-450 enzymes have been postulated to oxidize amines through a variety of mechanisms. One of the means of distinguishing among potential pathways involves the use of kinetic hydrogen isotope effects: low isotope effects are characteristic of aminium radical mechanisms while high values are consistent with hydrogen atom abstraction, a process documented in alkane hydroxylation. Nifedipine [1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylic+ ++ acid dimethyl ester] was prepared with isotopic substitution at the 4-position and utilized in determinations of the deuterium and tritium kinetic isotope effects. The noncompetitive intermolecular deuterium [DV, D(V/K)] and competitive intermolecular tritium [T(V/K)] isotope effects observed in the oxidation of nifedipine with liver microsomes prepared from untreated male rats were less than 2. Similar low deuterium and tritium isotope effects (less than 2) were also found with six other types of rat liver microsomal preparations and with three different human liver microsomal preparations, even though the rates of oxidation (expressed per nanomole of total cytochrome P-450) varied by an order of magnitude and other investigations indicate that several different cytochrome P-450 enzymes can catalyze the reaction. Similar low deuterium and tritium isotope effects were measured with a purified rat liver cytochrome P-450 preparation and horseradish peroxidase. These results are interpreted in terms of an electron/proton/electron transfer mechanism previously postulated for the oxidation of other dihydropyridines by cytochrome P-450 enzymes and model one-electron acceptors and argue against a mechanism involving hydrogen atom abstraction from nifedipine.


Chem Res Toxicol


Guengerich FP




Has Abstract


1990-01-01 00:00:00












  • Gamma-radiolysis and hydroxyl radical produce interstrand cross-links in DNA involving thymidine.

    abstract::Interstrand cross-links are minor components of the collection of products formed in DNA by ionizing radiation. Through their formation by other damaging agents, it is known that interstrand cross-links exert significant effects on replication and transcription. The structures of DNA interstrand cross-links produced a...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Ding H,Greenberg MM

    更新日期:2007-11-01 00:00:00

  • Catechin metabolism: glutathione conjugate formation catalyzed by tyrosinase, peroxidase, and cytochrome p450.

    abstract::The metabolic pathways of dietary flavonoids are still largely unknown. In the present work, mass spectrometry and UV-vis spectroscopy studies were used to show that the naturally occurring flavonoid catechin underwent enzymatic oxidation by tyrosinase in the presence of glutathione (GSH) to form mono-, bi-, and tri-g...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Moridani MY,Scobie H,Salehi P,O'Brien PJ

    更新日期:2001-07-01 00:00:00

  • Endogenous interleukin-4 regulates glutathione synthesis following acetaminophen-induced liver injury in mice.

    abstract::In a recent study, we reported that interleukin (IL)-4 had a protective role against acetaminophen (APAP)-induced liver injury (AILI), although the mechanism of protection was unclear. Here, we carried out more detailed investigations and have shown that one way IL-4 may control the severity of AILI is by regulating g...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Ryan PM,Bourdi M,Korrapati MC,Proctor WR,Vasquez RA,Yee SB,Quinn TD,Chakraborty M,Pohl LR

    更新日期:2012-01-13 00:00:00

  • Photomutagenicity of anhydroretinol and 5,6-epoxyretinyl palmitate in mouse lymphoma cells.

    abstract::Retinyl palmitate (RP) is frequently used as an ingredient in cosmetics and other retail products. We previously reported that, under UVA light irradiation, RP is facilely decomposed into multiple products, including anhydroretinol (AR) and 5,6-epoxyretinyl palmitate (5,6-epoxy-RP). We also determined that combined tr...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Mei N,Xia Q,Chen L,Moore MM,Chen T,Fu PP

    更新日期:2006-11-01 00:00:00

  • AHR- and DNA-damage-mediated gene expression responses induced by benzo(a)pyrene in human cell lines.

    abstract::Carcinogens induce complex transcriptional responses in cells that may hold key mechanistic information. Benzo(a)pyrene (BaP) modulation of transcription may occur through the activation of the aryl hydrocarbon receptor (AHR) or through responses to DNA damage. To characterize further the expression profiles induced b...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Hockley SL,Arlt VM,Brewer D,Te Poele R,Workman P,Giddings I,Phillips DH

    更新日期:2007-12-01 00:00:00

  • In vitro reaction with DNA of the fjord-region diol epoxides of benzo[g]chrysene and benzo[c]phenanthrene as studied by 32P-postlabeling.

    abstract::The chemical reactivities of the optically-pure fjord-region syn- and anti-benzo[g]chrysene 11,12-dihydrodiol 13,14-epoxides (B[g]CDEs) toward DNA in vitro have been compared with those of the optically-pure fjord-region syn- and anti-benzo[c]phenanthrene 3,4-dihydrodiol 1,2-epoxides (B[c]PhDEs), using the standard 32...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Giles AS,Seidel A,Phillips DH

    更新日期:1995-06-01 00:00:00

  • Oxidation of aflatoxins and sterigmatocystin by human liver microsomes: significance of aflatoxin Q1 as a detoxication product of aflatoxin B1.

    abstract::Aflatoxin Q1 8,9-oxide was synthesized and found to yield lower levels of N7-guanyl adducts than obtained from aflatoxin B1 8,9-oxide when mixed with calf thymus DNA or Salmonella typhimurium TA 98 cells. However, when S. typhimurium TA 98 was treated with the (analogous) epoxides of aflatoxin B1, aflatoxin G1, aflato...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Raney KD,Shimada T,Kim DH,Groopman JD,Harris TM,Guengerich FP

    更新日期:1992-03-01 00:00:00

  • Development of a partition-controlled dosing system for cell assays.

    abstract::Hydrophobic and volatile chemicals have proven to be difficult to dose in cell assays. Cosolvents are often needed to dissolve these chemicals in cell culture medium. Moreover, the free concentration of these chemicals in culture medium may diminish over time due to metabolism, evaporation, and nonspecific binding to ...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Kramer NI,Busser FJ,Oosterwijk MT,Schirmer K,Escher BI,Hermens JL

    更新日期:2010-11-15 00:00:00

  • 42,43,44,45,46,47,55-Heptanor-41-oxohomoyessotoxin, a new biotoxin from mussels of the northern Adriatic sea.

    abstract::The diarrhetic shellfish toxin composition in the digestive glands of mussels from the northern Adriatic sea was investigated. Along with known yessotoxins, identified by comparison of their chromatographic and spectral properties with those reported in the literature, we isolated a new analogue of yessotoxin, 42,43,4...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Ciminiello P,Fattorusso E,Forino M,Poletti R

    更新日期:2001-05-01 00:00:00

  • Biotransformation pathways of biocides and pharmaceuticals in freshwater crustaceans based on structure elucidation of metabolites using high resolution mass spectrometry.

    abstract::So far, there is limited information on biotransformation mechanisms and products of polar contaminants in freshwater crustaceans. In the present study, metabolites of biocides and pharmaceuticals formed in Gammarus pulex and Daphnia magna were identified using liquid chromatography-high resolution mass spectrometry. ...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Jeon J,Kurth D,Hollender J

    更新日期:2013-03-18 00:00:00

  • Common E-Cigarette Flavoring Chemicals Impair Neutrophil Phagocytosis and Oxidative Burst.

    abstract::E-cigarette flavorings have not been thoroughly evaluated for inhalational toxicity. We have shown that the flavoring chemical cinnamaldehyde impairs human neutrophils, macrophages, and natural killer cells. Here we investigated the effects of other common e-liquid flavoring chemicals on phagocytosis and oxidative bur...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Hickman E,Herrera CA,Jaspers I

    更新日期:2019-06-17 00:00:00

  • Alkylation of DNA by 1,3-dialkyl-3-acyltriazenes: correlation of biological activity with chemical behavior.

    abstract::The reactions of calf thymus DNA with four 1,3-dialkyl-3-acyltriazenes were studied alone or in the presence of pig liver esterase in pH 7.4 phosphate buffer for varying lengths of time. The best alkylating agent in the absence of esterase was determined to be 1,3-dimethyl-3-carbethoxytriazene (DMC), followed in order...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Kroeger-Koepke MB,Michejda CJ,Smith RH Jr

    更新日期:1992-07-01 00:00:00

  • Verification of the structural alerts for Michael acceptors.

    abstract::A diverse series of polarized alpha,beta-unsaturated and related compounds were evaluated for reactivity with a spectrophotometric assay using the sulfhydryl group in the form of the cysteine residue of the tripeptide GSH as a model nucleophile. The reactive end point (RC 50) calculations were compared to previously d...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Schultz TW,Yarbrough JW,Hunter RS,Aptula AO

    更新日期:2007-09-01 00:00:00

  • Fatty Acid Remodeling of Membrane Glycerophospholipids Induced by Bleomycin and Iron Oxide Nanoparticles in Human Embryonic Kidney Cells.

    abstract::Bleomycin has a long-studied mechanism of action through the formation of a complex with metals, such as iron. The bleomycin-iron complex was recently shown to induce membrane damage by free radical reactivity. Because the use of Fe nanoparticles is spreading for drug delivery strategies, molecular mechanisms of cell ...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Krokidis MG,Louka M,Efthimiadou EK,Ferreri C,Chatgilialoglu C

    更新日期:2020-10-19 00:00:00

  • Accumulation of manganese in the brain of mice after intravenous injection of manganese-based contrast agents.

    abstract::Because the manganese-based contrast agents used in magnetic, resonance imaging are unstable in vivo, some concern exists about the potential toxicity coming from the Mn2+ released by the complexes. This potential problem arises because the manganese is known to accumulate in the brain of people intoxicated by this me...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Gallez B,Baudelet C,Adline J,Geurts M,Delzenne N

    更新日期:1997-04-01 00:00:00

  • Notopterygium forbesii boiss extract and its active constituents increase reactive species and heme oxygenase-1 in human fetal hepatocytes: mechanisms of action.

    abstract::Notopterygium forbesii Boiss (NF) has been used as a traditional Chinese medicine for the treatment of common cold and rheumatism. However, there has been limited research on the biological properties of NF, and the mechanisms of action remain unknown. Here, we aimed to study the mechanism of NF-induced heme oxygenase...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Tang SY,Wang H,Zhang W,Halliwell B

    更新日期:2008-12-01 00:00:00

  • Reactivity with Tris(hydroxymethyl)aminomethane confounds immunodetection of acrolein-adducted proteins.

    abstract::The toxic alpha,beta-unsaturated aldehyde acrolein readily attacks proteins, generating adducts at cysteine, histidine, and lysine residues. In this study, rabbit antiserum was raised against acrolein-modified keyhole limpet hemocyanin in the expectation that it would allow immunodetection of adducted proteins in biol...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Burcham PC,Fontaine FR,Petersen DR,Pyke SM

    更新日期:2003-10-01 00:00:00

  • Distinct endoplasmic reticulum signaling pathways regulate apoptotic and necrotic cell death following iodoacetamide treatment.

    abstract::Environmental stress induces the synthesis of glucose-regulated proteins (Grps) in the endoplasmic reticulum (ER) and heat shock proteins (Hsps) in the cytoplasm. Iodoacetamide (IDAM), a prototypical alkyating agent, induces both Grp and Hsp synthesis in renal epithelial cells and causes necrosis which is prevented by...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: van De Water B,Wang Y,Asmellash S,Liu H,Zhan Y,Miller E,Stevens JL

    更新日期:1999-10-01 00:00:00

  • Base flipping free energy profiles for damaged and undamaged DNA.

    abstract::Lesion-induced thermodynamic destabilization is believed to facilitate β-hairpin intrusion by the human XPC/hHR23B nucleotide excision repair (NER) recognition factor, accompanied by partner-base flipping, as suggested by the crystal structure of the yeast orthologue (Min, J. H., and Pavletich, N. P. (2007) Nature 449...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Zheng H,Cai Y,Ding S,Tang Y,Kropachev K,Zhou Y,Wang L,Wang S,Geacintov NE,Zhang Y,Broyde S

    更新日期:2010-12-20 00:00:00

  • Chemical speciation of trivalent actinides and lanthanides in biological fluids: the dominant in vitro binding form of curium(III) and europium(III) in human urine.

    abstract::Radionuclides represent a serious health risk to humans in the case of incorporation. To elucidate the potential of time-resolved laser-induced fluorescence spectroscopy (TRLFS) to determine the dominant radionuclide species in natural biofluids, we investigated the in vitro speciation of curium(III) in human urine sa...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Heller A,Barkleit A,Bernhard G

    更新日期:2011-02-18 00:00:00

  • Titanium nanoparticle inhalation induces renal fibrosis in mice via an oxidative stress upregulated transforming growth factor-β pathway.

    abstract::Titanium dioxide nanoparticles (Nano-TiO2) are gradually being used extensively in clinical settings, industry, and daily life. Accumulation studies showed that Nano-TiO2 exposure is able to cause injuries in various animal organs, including the lung, liver, spleen, and kidney. However, it remains unclear whether expo...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Huang KT,Wu CT,Huang KH,Lin WC,Chen CM,Guan SS,Chiang CK,Liu SH

    更新日期:2015-03-16 00:00:00

  • Chemometric models for toxicity classification based on NMR spectra of biofluids.

    abstract::1H NMR spectroscopic and pattern recognition (PR)-based methods were used to investigate the biochemical variability in urine obtained from control rats and from rats treated with a hydrazine (a model hepatotoxin) or HgCl(2) (a model renal cortical toxin). The 600 MHz (1)H NMR spectra of urine samples obtained from ve...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Holmes E,Nicholls AW,Lindon JC,Connor SC,Connelly JC,Haselden JN,Damment SJ,Spraul M,Neidig P,Nicholson JK

    更新日期:2000-06-01 00:00:00

  • Obtaining exposures of metabolites in preclinical species through plasma pooling and quantitative NMR: addressing metabolites in safety testing (MIST) guidance without using radiolabeled compounds and chemically synthesized metabolite standards.

    abstract::The recent guidance on "Safety Testing of Drug Metabolites" issued by the U.S. Food and Drug Administration, Center for Drug Evaluation and Research (CDER) has highlighted the importance of identifying and characterizing drug metabolites as early as possible in drug discovery and development. Furthermore, upon identif...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Vishwanathan K,Babalola K,Wang J,Espina R,Yu L,Adedoyin A,Talaat R,Mutlib A,Scatina J

    更新日期:2009-02-01 00:00:00

  • Polychlorinated Biphenyl Quinone Induces Caspase 1-Mediated Pyroptosis through Induction of Pro-inflammatory HMGB1-TLR4-NLRP3-GSDMD Signal Axis.

    abstract::Polychlorinated biphenyls (PCBs) are one of the most refractory environmental pollutants. Because of their ubiquitous existence in the biological systems (including human body), it is important to investigate their toxic behavior. Our previous findings demonstrated that a high reactive metabolite of PCB, namely PCB29-...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Dong W,Zhu Q,Yang B,Qin Q,Wang Y,Xia X,Zhu X,Liu Z,Song E,Song Y

    更新日期:2019-06-17 00:00:00

  • A novel procedure for generating both nitric oxide and superoxide in situ from chemical sources at any chosen mole ratio. First application: tyrosine oxidation and a comparison with preformed peroxynitrite.

    abstract::The first method for generating (*)NO and O(2)(*)(-) at any known, constant ratio has been developed. Spermine NONOate and di(4-carboxybenzyl)hyponitrite decay with first-order kinetics and exactly equal rate constants (half-lives of 80 min) at 37 degrees C and pH 7.5 to give 200 and 40 mol % (*)NO and O(2)(*)(-), res...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Hodges GR,Marwaha J,Paul T,Ingold KU

    更新日期:2000-12-01 00:00:00

  • Diclofenac Sodium Triggers p53-Dependent Apoptosis in Human Corneal Epithelial Cells via ROS-Mediated Crosstalk.

    abstract::Diclofenac sodium (DFS), a nonsteroidal anti-inflammatory drug, is frequently used in ophthalmology, but it causes negative effects on corneas. The mechanisms underlying the toxicities to corneas remains unclear. The present study was designed to assess the cytotoxicity of DFS to human corneal epithelial (HCEP) cells ...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Li H,Fan TJ,Zou P,Xu B

    更新日期:2021-01-18 00:00:00

  • Cytochrome P450 Mediated Bioactivation of Rutaevin, a Bioactive and Potentially Hepatotoxic Component of Evodia Rutaecarpa.

    abstract::Rutaevin is one of the major bioactive constituents isolated from Evodia rutaecarpa, a well-known herbal medicine that has been widely prescribed for the treatment of gastrointestinal disorders in China. However, oral administration of rutaevin has been shown to cause hepatotoxicity in mice. Bioactivation was suggeste...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Liu Y,Liu C,Liu Y,Ge Q,Sun C

    更新日期:2020-12-21 00:00:00

  • Toxicant Deposition and Transport in Alveolus: A Classical Density Functional Prediction.

    abstract::The deposition and transport of toxicants on pulmonary surfactant are important processes in human health and medical care. We have introduced classical density functional theory (CDFT) to provide insight into this process. Nine typical toxicants in PM2.5 were considered, and their free energy and structural informati...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Liu H,Liu Y,Shang Y,Liu H

    更新日期:2018-12-17 00:00:00

  • Allyl alcohol activation of protein kinase C delta leads to cytotoxicity of rat hepatocytes.

    abstract::Hepatotoxicity of allyl alcohol involves its bioactivation to acrolein and subsequent protein sulfhydryl loss and lipid peroxidation. However, the links between these events and hepatocellular death are not known. The purpose of these studies was to examine whether specific signal transduction pathways are associated ...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Maddox JF,Roth RA,Ganey PE

    更新日期:2003-05-01 00:00:00

  • (5'S)- and (5'R)-5',8-cyclo-2'-deoxyguanosine: mechanistic insights on the 2'-deoxyguanosin-5'-yl radical cyclization.

    abstract::The two diastereomeric forms (5'S) and (5'R) of 5',8-cyclo-2'-deoxyguanosine have been synthesized and fully characterized. They have been used as references for the investigation of gamma-irradiation of 2'-deoxyguanosine and photolysis of 8-bromo-2'-deoxyguanosine in aqueous solutions. The observed (5'R)/(5'S) ratio ...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Chatgilialoglu C,Bazzanini R,Jimenez LB,Miranda MA

    更新日期:2007-12-01 00:00:00