Abstract:
: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.
journal_name
Chem Res Toxicoljournal_title
Chemical research in toxicologyauthors
Guengerich FPdoi
10.1021/tx00013a004subject
Has Abstractpub_date
1990-01-01 00:00:00pages
21-6issue
1eissn
0893-228Xissn
1520-5010journal_volume
3pub_type
杂志文章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
doi:10.1021/tx970227g
更新日期:1998-07-01 00:00:00
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...
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更新日期:2003-07-01 00:00:00
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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
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更新日期:2009-06-01 00:00:00
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
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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
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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 ...
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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
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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
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journal_title:Chemical research in toxicology
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更新日期:2003-04-01 00:00:00
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
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更新日期:2013-10-21 00:00:00
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
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更新日期:2015-05-18 00:00:00
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
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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
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更新日期:2014-01-21 00:00:00
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...
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更新日期:2017-07-17 00:00:00
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...
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doi:10.1021/acs.chemrestox.9b00391
更新日期:2020-09-21 00:00:00
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journal_title:Chemical research in toxicology
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更新日期:2007-03-01 00:00:00
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...
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journal_title:Chemical research in toxicology
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journal_title:Chemical research in toxicology
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更新日期:2011-06-20 00:00:00
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
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更新日期:1999-06-01 00:00:00
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
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更新日期:2013-08-19 00:00:00
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
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更新日期:2012-03-19 00:00:00
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
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更新日期:2018-08-20 00:00:00
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
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更新日期:2008-04-01 00:00:00
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
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doi:10.1021/acs.chemrestox.9b00392
更新日期:2020-02-17 00:00:00
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
doi:10.1021/tx0000163
更新日期:2000-08-01 00:00:00
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
doi:10.1021/acs.chemrestox.0c00162
更新日期:2020-10-19 00:00:00