Abstract:
:Raloxifene is a selective estrogen receptor modulator which is effective in the treatment of osteoporosis in postmenopausal women. We report herein that cytochrome P450 (P450)3A4 is inhibited by raloxifene in human liver microsomal incubations. The nature of the inhibition was irreversible and was NADPH- and preincubation time-dependent, with K(I) and k(inact) values estimated at 9.9 microM and 0.16 min(-1), respectively. The observed loss of P450 3A4 activity was attenuated partially by glutathione (GSH), implying the involvement of a reactive metabolite(s) in the inactivation process. Subsequently, GSH adducts of raloxifene were identified in incubations with human liver microsomes; substitution with GSH occurred at the 5- or 7-position of the benzothiophene moiety or at the 3'-position of the phenol ring, with the 7-glutathionyl derivative being most abundant based on LC/MS and NMR analyses. These adducts are postulated to derive from addition of GSH to raloxifene arene oxides followed by dehydration and aromatization. Alternatively, raloxifene may be oxidized to an extended quinone intermediate, which then is trapped by GSH conjugation. The bioactivation of raloxifene most likely is catalyzed by P450 3A4, since the formation of GSH adducts was almost abolished when liver microsomes were pretreated with ketoconazole or with an inhibitory anti-P450 3A4 IgG. The GSH adducts also were detected in incubations of raloxifene with rat or human hepatocytes, while the corresponding N-acetylcysteine adducts were identified in the bile and urine from rats treated orally with the drug at 5 mg/kg. Taken together, these data indicate that P450 3A4-mediated bioactivation of raloxifene in vitro is accompanied by loss of enzyme activity. The significance of these findings with respect to the clinical use of raloxifene remains to be determined.
journal_name
Chem Res Toxicoljournal_title
Chemical research in toxicologyauthors
Chen Q,Ngui JS,Doss GA,Wang RW,Cai X,DiNinno FP,Blizzard TA,Hammond ML,Stearns RA,Evans DC,Baillie TA,Tang Wdoi
10.1021/tx0200109subject
Has Abstractpub_date
2002-07-01 00:00:00pages
907-14issue
7eissn
0893-228Xissn
1520-5010pii
tx0200109journal_volume
15pub_type
杂志文章abstract::The worldwide outbreak of COVID-19 has drastically increased pressure on medical resources and highlighted the need for rapidly available, large-scale, and low-cost personal protective equipment (PPE). In this work, an alternative full-face mask is adapted from a modified snorkel mask to be used as PPE with two medica...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.0c00371
更新日期:2021-01-18 00:00:00
abstract::Oxidation of the tris(p-carboxyltetrathiaaryl)methyl (TAM) EPR radical probe, TAMa(•), by rat liver microsomes (RLM) + NADPH, or horseradish peroxidase (HRP) + H2O2, or K2IrCl6, led to an intermediate cation, TAMa(+), which was treated with glutathione (GSH), with formation of an adduct, TAMa-SG(•), resulting from the...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx400467p
更新日期:2014-04-21 00:00:00
abstract::Complex formation between nitrosoglutathione (GSNO) and Zn(II), Cd(II), and Ni(II) ions was studied by potentiometry and spectroscopic techniques. GSNO forms simple ML and ML2 type complexes (L = GSNO) with these ions. The stability of GSNO in HEPES buffer solution, pH 7.4, increased in the presence of both Zn(II) and...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx034194i
更新日期:2004-03-01 00:00:00
abstract::There is considerable evidence for the exposure of humans to an unknown ethylating agent, and some studies indicate that cigarette smoking may be one source of this exposure. Therefore, we have developed a liquid chromatography-nanoelectrospray-high resolution tandem mass spectrometry-selected reaction monitoring (LC-...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx200262d
更新日期:2011-10-17 00:00:00
abstract::2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a heterocyclic aromatic amine that is formed during the cooking of meats and poultry. PhIP is a carcinogen in rodents and a potential human carcinogen. Several short-term biomarkers of PhIP have been established for human biomonitoring, but validated long-term ...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx2003504
更新日期:2011-11-21 00:00:00
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
doi:10.1021/tx050089s
更新日期:2005-07-01 00:00:00
abstract::Exposures to sulfur mustard (HD; bis(2-chloroethyll) sulfide) are well-known to result in the formation of adducts with free aspartate and glutamate residues of plasma proteins (Lawrence, R. J., Smith, J. R., and Capacio, B. R. 2008 32, (1), 31-36). A modified version of the analytical method reported previously for t...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.0c00134
更新日期:2020-07-20 00:00:00
abstract::The relation between organophosphorus-induced delayed neuropathy (OPIDN) and brain neuropathy target esterase (NTE) inhibition is further examined in hens by structure-activity studies leading to the most potent in vitro NTE inhibitors known, which are then examined for their neuropathic effects in vivo in hens. The p...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx00050a011
更新日期:1995-12-01 00:00:00
abstract::N(6)-(2-Hydroxy-3-buten-1-yl)-2'-deoxyadenosine (N(6)-HB-dA I) and N(6),N(6)-(2,3-dihydroxybutan-1,4-diyl)-2'-deoxyadenosine (N(6),N(6)-DHB-dA) are exocyclic DNA adducts formed upon alkylation of the N(6) position of adenine in DNA by epoxide metabolites of 1,3-butadiene (BD), a common industrial and environmental che...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.5b00166
更新日期:2015-07-20 00:00:00
abstract::Human exposure to abacavir, a primary alcohol antiretroviral, is associated with the development of immunological drug reactions in individuals carrying the HLA risk allele B*57:01. Interaction of abacavir with antigen presenting cells results in cell activation through an Hsp70-mediated Toll-like receptor pathway and...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx400041v
更新日期:2013-07-15 00:00:00
abstract::The hepatic metabolism of microcystins (MCs), potent cyclic peptide hepatotoxins produced by cyanobacteria, was studied by i.p. injection in mice and rats. An immunoaffinity purification method using an anti-MC-LR monoclonal antibody showed a remarkable effect on the removal of contaminants in the hepatic cytosol and ...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx960085a
更新日期:1996-12-01 00:00:00
abstract::In this study, the HPLC, UV-vis, LC-MS, and 1H NMR characteristics of 14 different phase II mono- and mixed conjugates of quercetin were determined, providing a useful tool in the identification of quercetin phase II metabolite patterns in various biological systems. Using these data, the phase II metabolism of querce...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx049826v
更新日期:2004-11-01 00:00:00
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
doi:10.1021/tx1003613
更新日期:2010-12-20 00:00:00
abstract::A liquid chromatography electrospray tandem mass spectrometry (LC-ESI-MS/MS) method for the measurement of aflatoxin biomarkers in urine has been developed and validated. The two major aflatoxin-DNA adducts formed in rat tissues, aflatoxin N(7)-guanine and its imidazole ring opened derivative, 8,9-dihydro-8-(2,6-diami...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx010063a
更新日期:2001-07-01 00:00:00
abstract::The role of prostaglandin H synthase-1 (PHS-1) and a related model enzyme, horseradish peroxidase (HRP), in catalyzing the bioactivation of dopamine (DA) and epinephrine and their precursors and metabolites to potential neurodegenerative free radical intermediates was examined. To determine the potential contribution ...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx800423s
更新日期:2009-05-01 00:00:00
abstract::Hypoxia-inducible factor-1α (HIF-1α) is a critical regulator of cellular responses to hypoxia. Under normoxic conditions, the cellular HIF-1α level is regulated by hydroxylation by prolyl hydroxylases (PHDs), ubiquitylation, and proteasomal degradation. During hypoxia, degradation decreases, and its intracellular leve...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx300274a
更新日期:2012-10-15 00:00:00
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
doi:10.1021/tx00028a013
更新日期:1992-07-01 00:00:00
abstract::The growth-promoting effects of estrogens in hormone-dependent tumor tissues involve receptor-mediated pathways that are well-recognized; however, the role of estrogens in tumor initiation remains controversial. Estrogen metabolites, primarily the catechol estrogens (CE's), have been implicated in tumor initiation via...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx980128i
更新日期:1999-03-01 00:00:00
abstract::Developmental and reproductive toxicity (DART) end points are important hazard end points that need to be addressed in the risk assessment of chemicals to determine whether or not they are the critical effects in the overall risk assessment. These hazard end points are difficult to predict using current in silico tool...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx400226u
更新日期:2013-12-16 00:00:00
abstract::The binding conformations of single anti- and syn-BPDE-N2-dG adducts in oligonucleotides of varying base composition have been studied by induced circular dichroism (ICD) and light absorption spectroscopy. The sign of the ICD in single-stranded oligonucleotide adducts correlates with the absolute configuration of the ...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx9702244
更新日期:1999-05-01 00:00:00
abstract::8-Oxo-7,8-dihydroguanine (G(O), 8-hydroxyguanine) in DNA is one of the most important oxidatively damaged bases and causes G:C → T:A substitution mutations. The Werner syndrome protein (WRN) is a cancer-related RecQ DNA helicase and plays many roles in DNA replication and repair. To examine the relationships between G...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx500418m
更新日期:2015-04-20 00:00:00
abstract::Tocopherols (alpha-, beta-, gamma-, and delta-Toc) and tocopheryl quinones (alpha-, beta-, gamma-, and delta-TQ) were recently suggested to modulate mitochondrial electron transfer in mammals. Intriguingly, Tocs and stigmatellin, a potent inhibitor of the mitochondrial cytochrome (cyt) bc(1) complex, possess a common ...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx900333f
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::There are discrepancies about whether chlorpyrifos is able to induce neurodevelopmental toxicity or not. We previously reported alterations in the pattern of expression of biomarker genes of differentiation in D3 mouse embryonic stem cells caused by chlorpyrifos and its metabolites chlorpyrifos-oxon and 3,5,6-trichlor...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx500051k
更新日期:2014-09-15 00:00:00
abstract::A model protein, ribonuclease A (bovine pancreas), was examined for its ability to coordinate Ni2+ and promote selective oxidation. In the presence of a peracid such as monopersulfate, HSO5-, nickel induced the monomeric RNase A to form dimers, trimers, tetramers, and higher oligomers without producing fragmentation o...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx960170i
更新日期:1997-03-01 00:00:00
abstract::The issue of the safety of drug metabolites in humans is a complex one. In this commentary, a proposal is made regarding how to deal with drug metabolites observed in humans such that the safety of these molecules can be assured. The human radiolabeled ADME study, in which metabolites are identified and quantified in ...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx0602012
更新日期:2006-12-01 00:00:00
abstract::Carcinogenic polycyclic aromatic hydrocarbons (PAH), e.g., benzo[a]pyrene (BaP), possess a bay region comprising an ortho-fused benzene ring. Benzo[ghi]perylene (BghiP) represents the group of PAHs lacking such a "classic" bay region and hence cannot be metabolically converted like BaP to bay region dihydrodiol epoxid...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx049698a
更新日期:2005-04-01 00:00:00
abstract::The biological response of bronchial epithelial cells to particles is associated with a sequestration of cell metal by the particle surface and a subsequent disruption in host iron homeostasis. The macrophage is the cell type resident in the respiratory tract that is most likely to make initial contact with inhaled pa...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.8b00301
更新日期:2019-09-16 00:00:00
abstract::2-Nitrosoamino-3,8-dimethylimidazo[4,5-f]quinoxaline (N-NO-MeIQx) is a nitrosation product of the food carcinogen 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and is proposed to form in vivo under inflammatory conditions. This study evaluated the stability and reactivity of N-NO-MeIQx to assess its possible r...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx050305x
更新日期:2006-02-01 00:00:00
abstract::Nuclei from human lymphoblast cells grown in culture were treated with [7-14C]-(+/-)-r-7,t-8-dihydroxy-t-9,t-10-epoxy-7,8,9,10- tetrahydrobenzo[a]pyrene (anti-BPDE), and the nucleosomal core histones were isolated for adduct studies by cryogenic fluorescence line narrowing spectroscopy. The four core histones H2A, H2B...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx00038a004
更新日期:1994-03-01 00:00:00