Abstract:
:The N-reduction of the centrally acting alpha 2-adrenoreceptor agonist guanoxabenz (Benzérial), an N-hydroxyamidinohydrazone, to the amidinohydrazone guanabenz (Wytensin, Hipten, Rexitene) by microsomal fractions from rabbits, pigs and humans has been detected in vitro. The conversion rates with rabbit microsomal fractions were markedly slower than those in the cases of fractions from humans and pigs. It was also possible to demonstrate the N-oxidation of guanabenz to guanoxabenz by the use of microsomal fractions from rabbits, pigs, and humans. Furthermore, the oxidation was also observed in reconstituted systems in the presence of enriched cytochrome P450 fractions, purified isoenzyme P450 2C3, and heterologously expressed P450 2C3 of the subforms 6 beta H and 6 beta L. The analyses were performed with a newly developed HPLC technique and were confirmed by LC-MS methods. The kinetic parameters determined for the metabolic cycle (bioreversible reactions) are indicative of a predominance of the reduction of guanoxabenz to guanabenz in vivo. Accordingly, guanoxabenz in part constitutes a prodrug of guanabenz. Examination of guanabenz and guanoxabenz for mutagenicity by means of the Ames test revealed that guanoxabenz has pronounced mutagenic effects in the strains TA 98 and TA 1537. Guanabenz did not exhibit mutagenicity so that the N-reduction of guanoxabenz has significance in terms of detoxification.
journal_name
Chem Res Toxicoljournal_title
Chemical research in toxicologyauthors
Clement B,Demesmaeker M,Linne Sdoi
10.1021/tx9502047subject
Has Abstractpub_date
1996-06-01 00:00:00pages
682-8issue
4eissn
0893-228Xissn
1520-5010pii
tx9502047journal_volume
9pub_type
杂志文章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::Nitric oxide (NO(•); nitrogen monoxide) is known to be a critical regulator of cell and tissue function through mechanisms that utilize its unique physicochemical properties as a small and uncharged free radical with limited reactivity. Here, the basic chemistry and biochemistry of NO(•) are summarized through the des...
journal_title:Chemical research in toxicology
pub_type: 杂志文章,评审
doi:10.1021/tx300042g
更新日期:2012-05-21 00:00:00
abstract::The seaweed Fucus vesiculosus is unusual when compared with other algal species, in that it can survive in toxic-metal-contaminated aquatic environments. The metallothionein gene has been identified in F. vesiculosus by Kille and co-workers (Morris, C. A., Nicolaus, B., Sampson, V., Harwood, J. L., and Kille, P. (1999...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx050206j
更新日期:2006-03-01 00:00:00
abstract::Human hemoglobin was alkylated with (+/-)-7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE) and then treated with aqueous (+/-)-3-amino-1,2-propanediol to convert alkylated carboxyl side chains to N-(2,3-dihydroxypropyl) amides. Tryptic peptides produced from the modified protein...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx00021a016
更新日期:1991-05-01 00:00:00
abstract::A series of alpha-(X-substituted-methyl)-gamma,gamma-dimethyl-gamma-butyrolactones (series 1), a series of alpha-(2-X-substituted-ethyl)-gamma,gamma-dimethyl-gamma-butyrolactones (series 2), where X is a leaving group, and the compound alpha-(3-bromopropyl)-gamma,gamma-butyrolactone (3) were synthesized. Their reactio...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx00039a005
更新日期:1994-05-01 00:00:00
abstract::The procarcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is the most abundant heterocyclic amine formed during the cooking of foods. Metabolism of PhIP by CYP1A2 differs substantially between humans and rodents, with more N2-hydroxylation (activation) and less 4'-hydroxylation (detoxication) in humans....
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx050136g
更新日期:2005-09-01 00:00:00
abstract::Glyoxal is generated endogenously from the degradation of glucose and the oxidation of carbohydrates, lipids, and the 2-deoxyribose moieties of DNA. Glyoxal is also widely used in industry and is present in cigarette smoke and food. Glyoxal can conjugate with nucleobases and proteins to give advanced glycation end pro...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx900286c
更新日期:2010-01-01 00:00:00
abstract::Depleted uranium (DU) is commonly used in military armor and munitions, and thus, exposure of soldiers and non-combatants is potentially frequent and widespread. DU is considered a suspected human carcinogen, affecting the bronchial cells of the lung. However, few investigations have studied DU in human bronchial cell...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx700026r
更新日期:2007-05-01 00:00:00
abstract::The monoamine oxidase B (MAO-B) catalyzed oxidation of amines has been proposed to proceed via a polar pathway, an initial single-electron transfer pathway and an initial hydrogen atom transfer pathway. Results from previous studies on selected N-cyclopropyl-4-substituted-1,2,3,6-tetrahydropyridine derivatives have le...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx960063o
更新日期:1996-09-01 00:00:00
abstract::Arsenic is one of the inorganic pollutants typically found in natural waters, and its toxic effects on the human body are currently of great concern. For this reason, the search for detoxifying agents that can be used in a so-called "chelation therapy" is of primary importance. However, to the aim of finding the therm...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.9b00506
更新日期:2020-04-20 00:00:00
abstract::The measurement of metabolites constitutes a useful tool for detection of exposure and in pharmacokinetic studies. Epoxidation with subsequent glutathione conjugation and mercapturic acid formation is an important deactivation pathway for naphthalene, a toxin which presumably causes lung disease. The mercapturic acid ...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx00033a006
更新日期:1993-05-01 00:00:00
abstract::Nitrofluorenes are mutagenic and carcinogenic environmental pollutants arising chiefly from combustion of fossil fuels. Nitro aromatic compounds undergo nitroreduction to N-hydroxy arylamines that bind to DNA directly or after O-esterification. This study analyzes the DNA binding and adducts from the in vitro nitrored...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx010172p
更新日期:2002-04-01 00:00:00
abstract::The effect of adduct stereochemistry on the susceptibility to hydrolysis by snake venom (VPD) and bovine spleen (SPD) phosphodiesterases was investigated with short deoxyoligonucleotides containing defined adducts derived from alkylation of the exocyclic 6-amino group of dA by polycyclic aromatic hydrocarbon diol epox...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx010092l
更新日期:2001-09-01 00:00:00
abstract::The present work aimed to elucidate whether the toxic effects of nickel oxide (NiO) nanoparticles (NPs) on the yeast Saccharomyces cerevisiae were associated with oxidative stress (OS) and what mechanisms may have contributed to this OS. Cells exposed to NiO NPs accumulated superoxide anions and hydrogen peroxide, whi...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.8b00022
更新日期:2018-08-20 00:00:00
abstract::Caffeine on alkaline hydrolysis produces caffeidine [1-methyl-4-(methylamino)-5-(N-methylcarbamoyl)imidazole] and caffeidine acid [N-[4-(5-carboxy-1-methylimidazolyl)]-N,N'-dimethylurea]. We now report the synthesis and chemical characterization of mononitrosocaffeidine [1-methyl-4-(N-methyl-N-nitrosoamino)-5-(N-methy...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx00031a008
更新日期:1993-01-01 00:00:00
abstract::The mechanisms underlying aryl hydrocarbon receptor (AHR) activation by agonists and circumstances that increase the sensitivity toward agonists and AHR inhibition by antagonists are diverse and still not fully understood. AHR antagonist, 2-methyl-2 H-pyrazole-3-carboxylic acid (2-methyl-4- o-tolylazo-phenyl)-amide, C...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.8b00371
更新日期:2019-04-15 00:00:00
abstract::The nuclear receptor human pregnane X receptor (hPXR) is a ligand-regulated transcription factor that responds to a wide range of endogenous and xenobiotic molecules. Upon activation with ligands, hPXR can increase induction levels of metabolic enzymes. Therefore, hPXR plays a critical role in drug metabolism and excr...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx200310j
更新日期:2011-10-17 00:00:00
abstract::Catechol estrogens (CE) are among the major metabolites of estrone (E1) and 17 beta-estradiol (E2). Oxidation of these metabolites to semiquinones and quinones could generate ultimate carcinogenic forms of E1 and E2. The 2,3- and 3,4-quinones of E1 and E2 were synthesized by MnO2 oxidation of the corresponding CE, fol...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx00030a016
更新日期:1992-11-01 00:00:00
abstract::N,N-Bis(2-chloroethyl)-p-aminophenylbutyric acid (chlorambucil, 1) is an orally administrated drug widely used in the chemotherapy of chronic lymphocytic leukemia. We have recently described a new metabolic path for the decomposition of 1 in human gastric juice based on its reactions with saliva-derived thiocyanate io...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx980122t
更新日期:1998-11-01 00:00:00
abstract::Pyrrolizidine alkaloids (PAs) are known hepatotoxins. The execution of the toxicities of the alkaloids requires metabolic activation. Protein modification by reactive metabolites of PAs has been suggested to be an important mechanism of the toxic actions of PAs. The objectives of the present study were to define the i...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.5b00488
更新日期:2016-03-21 00:00:00
abstract::Quantum dots (QDs) are a novel class of inorganic fluorophores which are gaining widespread recognition as a result of their exceptional photophysical properties and their applications as a biomarker and in molecular biomedical imaging. The aim of this study was to evaluate the in vivo genotoxicity in mice exposed to ...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx2000015
更新日期:2011-05-16 00:00:00
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
doi:10.1021/tx400156a
更新日期:2013-07-15 00:00:00
abstract::The administration of 3'-hydroxyacetanilide, a regioisomer of acetaminophen, to mice failed to produce hepatotoxicity even after the administration of diethyl maleate. In contrast, hepatotoxicity did occur when 3'-hydroxyacetanilide was administered to buthionine sulfoximine pretreated mice. Although the administratio...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx00020a014
更新日期:1991-03-01 00:00:00
abstract::The perfluorinated carboxylic acid, perfluoro-n-decanoic acid (PFDA), is a known peroxisome proliferator which displays toxicity in rodents. Using a paired-tracer first-pass extraction technique, the effect of PFDA on hepatic glucose transport was determined in the isolated perfused rat liver. In brief, livers isolate...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx00043a010
更新日期:1995-01-01 00:00:00
abstract::Exposure to fine particulate matter (PM2.5), of which secondary organic aerosol (SOA) is a major constituent, is linked to adverse health outcomes, including cardiovascular disease, lung cancer, and preterm birth. Atmospheric oxidation of isoprene, the most abundant nonmethane hydrocarbon emitted into Earth's atmosphe...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.9b00322
更新日期:2020-02-17 00:00:00
abstract::Epidemiological evidence suggests a lower incidence of Parkinson's disease in smokers than in nonsmokers. This evidence, together with the lower levels of brain monoamine oxidase (MAO) activity in smokers and the potential neuroprotective properties of MAO inhibitors, prompted studies which led to the isolation and ch...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx000224v
更新日期:2001-05-01 00:00:00
abstract::The hepatic carcinogen aflatoxin B1 (AFB1) is metabolized in the liver by at least four different P450s, all of which exhibit large interindividual differences in the expression levels. These differences could affect the individual risk of hepatocellular carcinoma (HCC). We investigated the metabolism of AFB1 in a pan...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx050358e
更新日期:2006-04-01 00:00:00
abstract::Benzo[a]pyrene diol epoxides (BPDEs) are the ultimate carcinogenic species of benzo[a]pyrene, a prototype polycyclic aromatic hydrocarbon (PAH). BPDE-modified DNA duplexes can adopt multiple conformations depending on the nature of the modified bases, the stereochemistry at the location of the covalent linkage, and th...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx050308+
更新日期:2006-02-01 00:00:00
abstract::The deamination of DNA bases by three alpha-nitrosaminoaldehydes, butylethanalnitrosamine, methylethanalnitrosamine, and N-nitroso-2-hydroxymorpholine (NHMOR), the direct metabolite of potent animal carcinogen N-nitrosodiethanolamine, was demonstrated by a set of in vitro experiments. The deamination of guanine, adeni...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx990126d
更新日期:2000-02-01 00:00:00
abstract::2'-Deoxyoxanosine (dOxo) is a novel DNA lesion produced from dGuo by reaction with nitrous acid or nitric oxide [Suzuki, T., Yamaoka, R., Nishi, M., Ide, H., and Makino, K. (1996) J. Am. Chem. Soc. 118, 2515-2516]. We investigated the reaction of dOxo with glycine (Gly) under physiological conditions. When 5 mM dOxo w...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx990164x
更新日期:2000-04-01 00:00:00