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












  • Selective inhibition of cytochrome P450 2E1 in vivo and in vitro with trans-1,2-dichloroethylene.

    abstract::The effect of trans-1,2-dichloroethylene (DCE), an inhibitor of cytochrome P450 (P450) 2E1, on the catalytic activities and total content of hepatic P450 was determined in vivo and in vitro. Hepatic microsomes were prepared from groups of rats prior to dosing and at 2, 5, 12, and 24 h postdosing, and total P450 conten...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Mathews JM,Etheridge AS,Raymer JH,Black SR,Pulliam DW Jr,Bucher JR

    更新日期:1998-07-01 00:00:00

  • Interaction of trivalent arsenicals with metallothionein.

    abstract::Arsenic is a human carcinogen, causing skin, bladder, and lung cancers. Although arsenic in drinking water affects millions of people worldwide, the mechanism(s) of action by which arsenic causes cancers is not known. Arsenic probably exerts some toxic effects by binding with proteins. However, few experimental data a...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Jiang G,Gong Z,Li XF,Cullen WR,Le XC

    更新日期:2003-07-01 00:00:00

  • Oxidation of a dimethylthiourea metabolite by iodine and acidified iodate: N,N'-dimethylaminoiminomethanesulfinic acid (1).

    abstract::The two major metabolites after S-oxygenation of dimethylthiourea (dimethylaminoiminomethane sulfinic acid, DMAIMSA, and dimethylaminoiminomethane sulfonic acid, DMAIMSOA) were synthesized and tested for their reactivities in the presence of mild oxidants, aqueous iodine and acidic iodate. The stoichiometry of the iod...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Otoikhian A,Simoyi RH,Petersen JL

    更新日期:2005-07-01 00:00:00

  • Enzymatic methylation of DNA in cultured human cells studied by stable isotope incorporation and mass spectrometry.

    abstract::Enzymatic methylation of cytosine residues in DNA, in conjunction with covalent histone modifications, establishes an epigenetic code essential for the proper control of gene expression in higher organisms. Once established during cellular differentiation, the epigenetic code must be faithfully transmitted to progeny ...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Herring JL,Rogstad DK,Sowers LC

    更新日期:2009-06-01 00:00:00

  • Improved efficacy of acylfulvene in colon cancer cells when combined with a nuclear excision repair inhibitor.

    abstract::The efficacy of DNA-damaging anticancer drugs is highly influenced by cellular DNA repair capacity, and by inhibiting the relevant DNA repair pathway, efficacy of alkylating agents may be increased. Therefore, combining DNA repair inhibitors with anticancer agents that selectively target tumor tissue should improve ca...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: van Midwoud PM,Sturla SJ

    更新日期:2013-11-18 00:00:00

  • Free energy profiles of base flipping in intercalative polycyclic aromatic hydrocarbon-damaged DNA duplexes: energetic and structural relationships to nucleotide excision repair susceptibility.

    abstract::The crystal structure of Rad4/Rad23, the yeast homolog of the human nucleotide excision repair (NER) lesion recognition factor XPC-RAD23B ( Min , J. H. and Pavletich , N. P. ( 2007 ) Nature 449 , 570 - 575 ) reveals that the lesion-partner base is flipped out of the helix and binds to amino acids of the protein. This ...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Cai Y,Zheng H,Ding S,Kropachev K,Schwaid AG,Tang Y,Mu H,Wang S,Geacintov NE,Zhang Y,Broyde S

    更新日期:2013-07-15 00:00:00

  • Fast-flow EPR spectroscopic observation of the isoniazid, iproniazid, and phenylhydrazine hydrazyl radicals.

    abstract::Hydrazyl radical intermediates have been suggested as important intermediates in the biochemistry of hydrazides and hydrazines. Although spin-trapping studies have intercepted those species previously, there has been no report of the direct observation of the unstable hydrazyl radicals of isoniazid and iproniazid. We ...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Sipe HJ Jr,Jaszewski AR,Mason RP

    更新日期:2004-02-01 00:00:00

  • Occupational Respiratory Exposure to Platinum Group Metals: A Review and Recommendations.

    abstract::Platinum group metals (PGMs) is a group of metals that include platinum, palladium, rhodium, ruthenium, iridium, and osmium. Occupational respiratory exposure to platinum has been reported since 1945, but studies investigating occupational exposure to palladium, rhodium, ruthenium, iridium, and osmium are scarce. This...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章,评审


    authors: Linde SJL,Franken A,du Plessis JL

    更新日期:2017-10-16 00:00:00

  • Pulmonary toxicity and metabolic activation of tetrandrine in CD-1 mice.

    abstract::Tetrandrine, a bisbenzylisoquinoline alkaloid, has demonstrated promising pharmacologic activities. The alkaloid has a great potential for clinical use, so a careful, thorough toxicity evaluation of the alkaloid is required. In the present study, 24 h acute toxicity of tetrandrine was evaluated in CD-1 mice. Single in...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Jin H,Li L,Zhong D,Liu J,Chen X,Zheng J

    更新日期:2011-12-19 00:00:00

  • Hypochlorous acid-mediated oxidation of lipid components and antioxidants present in low-density lipoproteins: absolute rate constants, product analysis, and computational modeling.

    abstract::Oxidation of low-density lipoproteins (LDL) is believed to contribute to the increased uptake of LDL by macrophages, which is an early event in atherosclerosis. Hypochlorous acid (HOCl) has been implicated as one of the major oxidants involved in these processes. In a previous study, the rates of reaction of HOCl with...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Pattison DI,Hawkins CL,Davies MJ

    更新日期:2003-04-01 00:00:00

  • Chromium(VI) causes interstrand DNA cross-linking in vitro but shows no hypersensitivity in cross-link repair-deficient human cells.

    abstract::Hexavalent chromium is a human carcinogen activated primarily by direct reduction with cellular ascorbate and to a lesser extent, by glutathione. Cr(III), the final product of Cr(VI) reduction, forms six bonds allowing intermolecular cross-linking. In this work, we investigated the ability of Cr(VI) to cause interstra...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Morse JL,Luczak MW,Zhitkovich A

    更新日期:2013-10-21 00:00:00

  • Reactive Sulfur Species-Mediated Activation of the Keap1-Nrf2 Pathway by 1,2-Naphthoquinone through Sulfenic Acids Formation under Oxidative Stress.

    abstract::Sulfhydration by a hydrogen sulfide anion and electrophile thiolation by reactive sulfur species (RSS) such as persulfides/polysulfides (e.g., R-S-SH/R-S-Sn-H(R)) are unique reactions in electrophilic signaling. Using 1,2-dihydroxynaphthalene-4-thioacetate (1,2-NQH2-SAc) as a precursor to 1,2-dihydroxynaphthalene-4-th...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Shinkai Y,Abiko Y,Ida T,Miura T,Kakehashi H,Ishii I,Nishida M,Sawa T,Akaike T,Kumagai Y

    更新日期:2015-05-18 00:00:00

  • In vitro model of mammary estrogen metabolism: structural and kinetic differences between catechol estrogens 2- and 4-hydroxyestradiol.

    abstract::Estrogens and their oxidative metabolites, the catechol estrogens, have been implicated in the development of breast cancer; yet, relatively little is known about estrogen metabolism in the breast. To determine how the parent hormone, 17 beta-estradiol (E(2)), is metabolized, we used recombinant, purified phase I enzy...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Dawling S,Hachey DL,Roodi N,Parl FF

    更新日期:2004-09-01 00:00:00

  • Mass spectrometric methods for the analysis of nucleoside-protein cross-links: application to oxopropenyl-deoxyadenosine.

    abstract::Electrophilic DNA adducts produced following oxidative stress can form DNA-protein cross-links (DPCs), dramatically altering genomic maintenance pathways. Complete characterization of DPCs has been hindered, in part, because of a lack of comprehensive techniques for their analysis. We have, therefore, established a pr...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Shuck SC,Rose KL,Marnett LJ

    更新日期:2014-01-21 00:00:00

  • Trends in Environmental Tobacco Smoke (ETS) Exposure and Preterm Birth: Use of Smoking Bans and Direct ETS Exposure Assessments in Study Designs.

    abstract::For decades, many studies have linked maternal smoking to an increased risk of preterm birth. As a result, the scientific community has long hypothesized that exposure to environmental tobacco smoke (ETS), commonly referred to as second-hand smoke, is also associated with an increased risk of preterm birth. Multiple s...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Elkin ER,O'Neill MS

    更新日期:2017-07-17 00:00:00

  • Mechanistic Insights into the Cytotoxicity of Graphene Oxide Derivatives in Mammalian Cells.

    abstract::Graphene oxide derivatives (GODs) have superb physical/chemical properties with promise for applications in biomedicine. Shape, size, and chemistry of the GODs are identified as the key parameters that impact any biological system. In this work, the GODs with a wide range of shapes (sheets, helical/longitudinal ribbon...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Lu P,Zehtab Yazdi A,Han XX,Al Husaini K,Haime J,Waye N,Chen P

    更新日期:2020-09-21 00:00:00

  • Abiotic sulfhydryl reactivity: a predictor of aquatic toxicity for carbonyl-containing alpha,beta-unsaturated compounds.

    abstract::A diverse series of aliphatic alpha,beta-unsaturated esters, ketones, and aldehydes were evaluated for reactivity with the model nucleophile sulfhydryl group in the form of the cysteine residue of the tripeptide glutathione; the reactive end point (RC50) was then related to aquatic toxicity (IGC50) assessed in the Tet...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Yarbrough JW,Schultz TW

    更新日期:2007-03-01 00:00:00

  • Glutathione Conjugation and Protein Adduction by Environmental Pollutant 2,4-Dichlorophenol In Vitro and In Vivo.

    abstract::2,4-Dichlorophenol (2,4-DCP), an environmental pollutant, was reported to cause hepatotoxicity. The biochemical mechanisms of 2,4-DCP induced liver injury remain unknown. The present study showed that 2,4-DCP is chemically reactive and spontaneously reacts with GSH and bovine serum albumin to form GSH conjugates and B...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Li Q,Li W,Zhao J,Guo X,Zou Q,Yang Z,Tian R,Peng Y,Zheng J

    更新日期:2020-09-21 00:00:00

  • Computational models for predicting the binding affinities of ligands for the wild-type androgen receptor and a mutated variant associated with human prostate cancer.

    abstract::In the present study, values of the binding energy (BE) were calculated for the rat androgen receptor on a data set of 25 steroidal and nonsteroidal compounds for which published values of the observed binding affinity (K(i)) are available. A correlation between BE and pK(i) was evident (r(2) = 0.50) for the entire da...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Ai N,DeLisle RK,Yu SJ,Welsh WJ

    更新日期:2003-12-01 00:00:00

  • Reaction of lysine with estrone 3,4-o-quinone.

    abstract::Reaction of lysine with estrone 3,4-o-quinone gave a complex mixture of products. Six compounds were isolated and identified using spectroscopic techniques. Among the reaction products isolated were 4-hydroxyestrone (2), 3-aminoisoestrone (3), 3-(N-pentyl-5-amino)-isoestrone (4), 1-lysylestrone 3,4-o-iminoquinone (5),...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Tabakovic K,Abul-Hajj YJ

    更新日期:1994-09-01 00:00:00

  • Two-Mechanism Model for the Interaction of Etoposide Quinone with Topoisomerase IIα.

    abstract::Topoisomerase II is an essential nuclear enzyme involved in regulating DNA topology to facilitate replication and cell division. Disruption of topoisomerase II function by chemotherapeutic agents is in use as an effective strategy to fight cancer. Etoposide is an anticancer therapeutic that disrupts the catalytic cycl...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Gibson EG,King MM,Mercer SL,Deweese JE

    更新日期:2016-09-19 00:00:00

  • Human glutathione transferases catalyzing the conjugation of the hepatoxin microcystin-LR.

    abstract::Many cyanobacterial species are able to produce cyanotoxins as secondary metabolites. Among them, microcystins (MC) are a group of around 80 congeners of toxic cyclic heptapeptides. MC-LR is the most studied MC congener, in view of its high acute hepatotoxicity and tumor promoting activity. Humans may be exposed to cy...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Buratti FM,Scardala S,Funari E,Testai E

    更新日期:2011-06-20 00:00:00

  • The nutritional supplement chromium(III) tris(picolinate) cleaves DNA.

    abstract::Chromium(III) tris(picolinate) [Cr(pic)3] is currently a very popular nutritional supplement; however, its safety has recently been questioned, especially with regard to its ability to act as a clastogen. At physiologically relevant concentrations, Cr(pic)3 is reduced by biological reductants, including ascorbate and ...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Speetjens JK,Collins RA,Vincent JB,Woski SA

    更新日期:1999-06-01 00:00:00

  • Etoposide catechol is an oxidizable topoisomerase II poison.

    abstract::Topoisomerase II regulates DNA topology by generating transient double-stranded breaks. The anticancer drug etoposide targets topoisomerase II and is associated with the formation of secondary leukemias in patients. The quinone and catechol metabolites of etoposide may contribute to strand breaks that trigger leukemic...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Jacob DA,Gibson EG,Mercer SL,Deweese JE

    更新日期:2013-08-19 00:00:00

  • Metabolomic characterization of laborers exposed to welding fumes.

    abstract::The complex composition of welding fumes, multiplicity of molecular targets, diverse cellular effects, and lifestyles associated with laborers vastly complicate the assessment of welding fume exposure. The urinary metabolomic profiles of 35 male welders and 16 male office workers at a Taiwanese shipyard were character...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Wang KC,Kuo CH,Tian TF,Tsai MH,Chiung YM,Hsiech CM,Tsai SJ,Wang SY,Tsai DM,Huang CC,Tseng YJ

    更新日期:2012-03-19 00:00:00

  • Reaction of CO2 with ONOO-: One Molecule of CO2 Is Not Enough.

    abstract::With CO2 present in excess, ONOO- reacts to form an adduct in solution and in the solid state, most likely ONOOCO2-. In solution, the adduct appears within 2 ms and absorbs at 300 with an extinction coefficient, which is either 50% or 100% (preferred) of that of ONOO-, 1.70 × 103 M-1 cm-1, and at 685 nm with an extinc...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Serrano-Luginbuehl S,Kissner R,Koppenol WH

    更新日期:2018-08-20 00:00:00

  • (-)-Epigallocatechin gallate, a major constituent of green tea, poisons human type II topoisomerases.

    abstract::(-)-Epigallocatechin gallate (EGCG) is the most abundant and biologically active polyphenol in green tea, and many of the therapeutic benefits of the beverage have been attributed to this compound. High concentrations of EGCG are cytotoxic and trigger genotoxic events in mammalian cells. Although this catechin affects...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Bandele OJ,Osheroff N

    更新日期:2008-04-01 00:00:00

  • Bioisosteric Replacement of Amide Group with 1,2,3-Triazoles in Acetaminophen Addresses Reactive Oxygen Species-Mediated Hepatotoxic Insult in Wistar Albino Rats.

    abstract::Acetaminophen (AP) is a popularly recommended over-the-counter analgesic-antipyretic in clinical use. However, the drug is handicapped by the occurrence of hepatotoxic insult following acute ingestion. Consequently, AP-induced hepatotoxicity is often implicated in accidental or suicidal overdose. In the current study,...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Sahu A,Das D,Sahu P,Mishra S,Sakthivel A,Gajbhiye A,Agrawal R

    更新日期:2020-02-17 00:00:00

  • Sex dependence of the components and structure of urinary calculi induced by biphenyl administration in rats.

    abstract::To obtain definitive information about the mechanisms of urinary calculus formation and the structural characteristics of the calculi induced by biphenyl administration in rats, with a focus on the sex dependency, the constituents of the urinary calculi were analyzed by HPLC, inductively coupled plasma spectroscopy (I...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章


    authors: Ohnishi M,Yajima H,Yamamoto S,Matsushima T,Ishii T

    更新日期:2000-08-01 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