Abstract：
:The clinically used antitumor antibiotic mitomycin C requires a reductive activation to be converted to a bis-electrophile that forms several covalent adducts with DNA, including an interstrand cross-link which is considered to be the lesion responsible for the cytotoxic effects of the drug. Enzymes such as cytochrome P450 reductase and DT-diaphorase have traditionally been implicated in the bioreduction of mitomycin C, but recent reports indicate that enzymes containing a dithiol active site are also involved in the metabolism of mitomycin C. The reductive activation can also be effected in vitro with chemical reductants, but until now, mitomycin C was considered to be inert to thiols. We report here that mitomycin C can, in fact, be reductively activated by thiols. We show that the reaction is autocatalytic and that the end product is a relatively stable aziridinomitosene that can be trapped by adding several nucleophiles after the activation reaction. Kinetic studies show that the reaction is highly sensitive to pH and does not proceed or proceeds very slowly at neutral pH, an observation that explains the unsuccessful results on previous attempts to activate mitomycin C with thiols. The optimum pH for the reactions is around the pK(a) values of the thiols used in the activation. A mechanism for the reaction is hypothesized, involving the initial formation of a thiolate-mitomycin adduct, that then evolves to give the hydroquinone of mitomycin C and disulfide. The results presented here provide a chemical mechanism to explain how some biological dithiols containing an unusually acidic thiol group (deprotonated at physiological pH) participate in the modulation of mitomycin C cytotoxicity.
journal_name
Chem Res Toxicoljournal_title
Chemical research in toxicologyauthors
Paz MMdoi
10.1021/tx9002758subject
Has Abstractpub_date
2009-10-01 00:00:00pages
1663-8issue
10eissn
0893-228Xissn
1520-5010journal_volume
22pub_type
杂志文章abstract：:Butadiene monoxide, a toxic metabolite of 1,3-butadiene, is a substrate for the human placental glutathione (GSH) S-transferase. The products have been identified as S-(2-hydroxy-3-buten-1-yl)glutathione (I) and S-(1-hydroxy-3-buten-2-yl)glutathione (II). S-(4-hydroxy-2-buten-1-yl)glutathione (III), which was formed c...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx00022a006
更新日期：1991-07-01 00:00:00
abstract：:Alzheimer's disease, the most common cause of dementia, is at epidemic proportions (15 to 44% depending on age, of those age 65 to 84) in the U.S. and other developed countries but remains relatively rare in undeveloped countries. Surprisingly, solid historical data reveal the epidemic is a creature of the last centur...
journal_title：Chemical research in toxicology
pub_type： 杂志文章,评审
doi：10.1021/acs.chemrestox.6b00373
更新日期：2017-03-20 00:00:00
abstract：:1,3-Butadiene (BD) is a high-volume industrial chemical and a common environmental pollutant. Although BD is classified as a "probable human carcinogen", only limited evidence is available for its tumorigenic effects in occupationally exposed populations. Animal studies show a surprisingly high sensitivity of mice to ...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx9700681
更新日期：1997-10-01 00:00:00
abstract：:Organically modified rectorite (OREC) micro/nanoparticles can be synthesized by organic modification from calcium rectorite (Ca(2+)-REC or REC), a common form of rectorite in nature. Although REC and OREC have potential applications in food packing and drug delivery, their cytotoxicity is not clear. In the present stu...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx500115p
更新日期：2014-08-18 00:00:00
abstract：:Stimulated monocytes and neutrophils generate hypochlorite (HOCl) via the release of the enzyme myeloperoxidase and hydrogen peroxide. HOCl is a key bactericidal agent, but can also damage host tissue. As there is a strong link between chronic inflammation and some cancers, we have investigated HOCl damage to DNA, RNA...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx015548d
更新日期：2002-01-01 00:00:00
abstract：:Copper is a physiologically important, redox-active metal that may be involved in endogenous DNA damage and mutagenesis. To understand the factors that affect the location and quantity of copper-induced oxidative DNA damage in cells, we used the 5S rDNA nucleosome as a model to assess the effect of chromatin structure...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx0002278
更新日期：2001-04-01 00:00:00
abstract：:Methylmercury (MeHg) reacts readily with GSH, leading to the formation of a MeHg-SG adduct that is excreted into extracellular space through multidrug-resistance-associated protein (MRP), which is regulated by the transcription factor Nrf2. We previously reported that MeHg covalently modifies Keap1 and activates Nrf2 ...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx5002332
更新日期：2014-10-20 00:00:00
abstract：:The rat esophagus is strikingly sensitive to tumor induction by nitrosamines, and it has been hypothesized that this tissue contains cytochrome P450 enzymes (P450s) which catalyze the metabolic activation of these carcinogens. The metabolic capacity of the esophagus is not well characterized. In the study described he...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx010065v
更新日期：2001-10-01 00:00:00
abstract：:8-Hydroxy-2'-deoxyguanosine (8-OHdG), a biomarker of oxidative DNA damage, has been extensively studied to assess human exposure to carcinogenic compounds. Previous studies have associated levels of human urinary hydroxylated polycyclic aromatic hydrocarbons (OH-PAHs) with those of 8-OHdG. However, measurements of OH-...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx200517h
更新日期：2012-02-20 00:00:00
abstract：:Metabolic bioactivation, glutathione depletion, and covalent binding are the early hallmark events after acetaminophen (APAP) overdose. However, the subsequent metabolic consequences contributing to APAP-induced hepatic necrosis and apoptosis have not been fully elucidated. In this study, serum metabolomes of control ...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx800464q
更新日期：2009-04-01 00:00:00
abstract：:Nitroaromatic compounds represent a major class of industrial chemicals that are also found in nature. Polycyclic derivatives are regarded as potent mutagens and carcinogens following bioactivation to produce nitrenium electrophiles that covalently modify DNA to afford N-linked C8-2'-deoxyguanosine (C8-dG) lesions tha...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/acs.chemrestox.9b00411
更新日期：2020-02-17 00:00:00
abstract：:Structure-function relationships for the inhibition of human cytochrome P450s (P450s) 1A1, 1A2, 1B1, 2C9, and 3A4 by 33 flavonoid derivatives were studied. Thirty-two of the 33 flavonoids tested produced reverse type I binding spectra with P450 1B1, and the potencies of binding were correlated with the abilities to in...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx100286d
更新日期：2010-12-20 00:00:00
abstract：:Electronic cigarette liquids (e-liquids) with sweetener additives such as sucralose, a synthetic chlorinated disaccharide, are popular among some e-cigarette consumers; sucralose can be added either by the manufacturer or by the consumer. The prevalence of sucralose in commercial e-liquids is not known, nor is the typ...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/acs.chemrestox.9b00047
更新日期：2019-06-17 00:00:00
abstract：:Previously, we identified two distinct metabonomic phenotypes in Sprague-Dawley rats sourced from two different rooms (colonies) in the Charles River, Raleigh facility [Robosky, L. C., Wells, D. F., Egnash, L. A., Manning, M. L., Reily, M. D., and Robertson, D. G. (2005) Metabonomic identification of two distinct phen...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx700184u
更新日期：2007-10-01 00:00:00
abstract：:A freely available Windows-based program, RNSim1A, is utilized to predict metal-independent reactive nitrogen species (RNS) chemistry (oxidation, nitrosation, and nitration) under simulated biological conditions and make the following specific predictions. (1) The peak in oxidative reactions that occurs in vitro with ...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx060061w
更新日期：2006-09-01 00:00:00
abstract：:Idiosyncratic drug reactions (IDRs) represent a major clinical problem, and at present, the mechanisms involved are still poorly understood. One animal model that we have used for mechanistic studies of IDRs is penicillamine-induced autoimmunity in Brown Norway (BN) rats. Previous work in our lab found that macrophage...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx900087z
更新日期：2009-07-01 00:00:00
abstract：:8-Aminoguanine had previously been identified as one of the nucleic acid base modifications produced in livers of rats by treatment with the hepatocarcinogen 2-nitropropane (2-NP), and a hypothetical mechanism of activation of 2-NP to hydroxylamine-O-sulfonate or acetate that would lead to NH2+, an aminating species, ...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx00039a011
更新日期：1994-05-01 00:00:00
abstract：:The metabolism of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) was investigated in five human volunteers given a dietary equivalent of 14C-labeled MeIQx. The amount of the dose excreted in urine ranged from 20.2% to 58.6%, with unmetabolized MeIQx accounting for 0.7-2.8% of the dose. Five principal metabolite...
journal_title：Chemical research in toxicology
pub_type： 临床试验,杂志文章
doi：10.1021/tx9701891
更新日期：1998-03-01 00:00:00
abstract：:2,5-Hexanedione (2,5-HD) is the neurotoxic gamma-diketone metabolite of the industrial solvent n-hexane. Substantial evidence indicates that 2,5-HD reacts with neurofilament protein lysine epsilon-amines to yield 2,5-dimethylpyrrole adducts and that this reaction is critical to the mechanism of toxicity. Alkylpyrroles...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx00040a011
更新日期：1994-07-01 00:00:00
abstract：:Successful early attrition of potential problematic compounds is of great importance in the pharmaceutical industry. The lead compound in a recent project targeting neuropathic pain was susceptible to metabolic bioactivation, which produced reactive metabolites and showed covalent binding to protein. Therefore, as a p...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx5000409
更新日期：2014-06-16 00:00:00
abstract：:Previously, we reported a new animal model of an idiosyncratic drug reaction in which nevirapine causes a skin rash in some rats that has characteristics similar to the reaction that occurs in humans. Strong evidence that the reaction is immune-mediated was found; specifically, low-dose pretreatment induced tolerance,...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx0501132
更新日期：2005-12-01 00:00:00
abstract：:Aminoglutethimide (AMG) is an aromatic amine aromatase inhibitor associated with a high incidence of idiosyncratic blood dyscrasias, especially agranulocytosis. Animal models of idiosyncratic drug reactions (IDRs) represent essential tools to study these reactions; however, there is currently no valid model of idiosyn...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx400224j
更新日期：2013-08-19 00:00:00
abstract：:The increasing use of fullerene nanomaterials has prompted widespread concern over their biological effects. Herein, we have studied the phototoxicity of gamma-cyclodextrin bicapped pristine C 60 [(gamma-CyD) 2/C 60] and its water-soluble derivative C 60(OH) 24 toward human keratinocytes. Our results demonstrated that...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx800056w
更新日期：2008-05-01 00:00:00
abstract：:Bezafibrate is a hypolipidemic drug that belongs to the group of peroxisome proliferators because it binds to peroxisome proliferator-activated receptors type alpha (PPARs). Peroxisome proliferators produce a myriad of extraperoxisomal effects, which are not necessarily dependent on their interaction with PPARs. An in...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx0341052
更新日期：2003-11-01 00:00:00
abstract：:Acetaminophen (APAP), a commonly used analgesic, is catalyzed by cytochrome P450 (P450) enzymes to a toxic intermediate which can be trapped by glutathione. Using this approach, involvement of enzymes in the activation of APAP and their kinetics were studied. With human liver microsomes, there were three apparent Km v...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx00034a019
更新日期：1993-07-01 00:00:00
abstract：:Spin-trapping with 5,5-dimethyl-1-pyrroline 1-oxide (DMPO) was used to demonstrate that 3-nitrotyrosine (nitrotyrosine) promotes the formation of substantial amounts of reactive oxygen species (O2.- and *OH), when incubated with NAD(H)-cytochrome c reductase and a corresponding electron donor. Spin adduct formation is...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx970201p
更新日期：1998-05-01 00:00:00
abstract：:The synthesis of a series of 1,2,4-triazole-containing oligopeptide lexitropsins related to the natural antitumor antibiotic distamycin is described. The binding properties of these new agents to both native DNAs and synthetic polydeoxyribonucleotides were determined by UV absorption and circular dichroism studies. Th...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx00020a019
更新日期：1991-03-01 00:00:00
abstract：:Oxidative stress is a commonly cited mechanism of toxicity of environmental agents. Ubiquitous environmental chemicals such as the diesel exhaust component 1,2-naphthoquinone (1,2-NQ) induce oxidative stress by redox cycling, which generates hydrogen peroxide (H2O2). Cysteinyl thiolate residues on regulatory proteins ...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/acs.chemrestox.5b00424
更新日期：2015-12-21 00:00:00
abstract：:Deferoxamine is an inhibitor of iron-dependent free radical reactions. Despite the antioxidant roles, prolonged clinical use of the chelator is far from benign, and paradoxically, deferoxamine has been shown to promote lipid peroxidation. The possible toxicity of the drug's metabolites, such as deferoxamine nitroxide ...
journal_title：Chemical research in toxicology
pub_type： 杂志文章
doi：10.1021/tx980212y
更新日期：1999-02-01 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
