Formation of glutathionyl-spironolactone disulfide by rat liver cytochromes P450 or hog liver flavin-containing monooxygenases: a functional probe of two-electron oxidations of the thiosteroid?

Abstract:

:We have previously reported that the diuretic thiosteroid spironolactone (SPL) inactivates rat liver microsomal cytochromes P450 [P450 (P450 3A and P450 2C11)] in a in a mechanism-based fashion, and we have identified two polar SPL metabolites (SPL-sulfinic acid and -sulfonic acid), formed in a partition ratio of approximately 20:1 in such rat liver microsomal incubations [Decker et al. (1989) Biochemistry 28, 5128-5136]. We proposed at the time that these metabolites were most likely derived from further enzymatic (or nonenzymatic) oxidations of the one-electron oxidation product [SPL-thiyl radical (SPL-S.)] and/or the two-electron-oxidized species [SPL-sulfenic acid (SPL-SOH)]. In those studies, glutathione (GSH) was found to attenuate both SPL-mediated P450 loss as well as polar metabolite formation by approximately 40%. We have now reexamined this in greater detail and report that it is due to GSH trapping of an electrophilic oxidized SPL species to form an adduct that we have isolated and unambiguously characterized by mass spectral analyses as the glutathionyl-SPL adduct (SPL-SSG). Moreover, we have found not only that rat liver microsomal formation of this adduct is enhanced at pH 9.0, the pH optimum for flavin-containing monooxygenase (FMO), but also that such adduct formation was indeed efficiently catalyzed by purified hog liver FMO. Because FMO oxidations of thiols are thought to entail a two-electron process to form the corresponding sulfenic acids, we infer that such a SPL-SSG adduct most likely reflects FMO-catalyzed oxidation of SPL to SPL-SOH, which on leaving the FMO active site is then trapped by GSH.(ABSTRACT TRUNCATED AT 250 WORDS)

journal_name

Chem Res Toxicol

authors

Decker CJ,Cashman JR,Sugiyama K,Maltby D,Correia MA

doi

10.1021/tx00024a012

subject

Has Abstract

pub_date

1991-11-01 00:00:00

pages

669-77

issue

6

eissn

0893-228X

issn

1520-5010

journal_volume

4

pub_type

杂志文章
  • Enhancement of 2'-deoxyguanosine hydroxylation and DNA damage by coal and oil fly ash in relation to particulate metal content and availability.

    abstract::Epidemiologic studies have shown causal relationships between air pollution particles and adverse health effects in susceptible subpopulations. Fly ash particles (containing water-soluble and insoluble metals) are a component of ambient air particulate pollution and may contribute to particulate-induced health effects...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章

    doi:10.1021/tx000110j

    authors: Prahalad AK,Inmon J,Ghio AJ,Gallagher JE

    更新日期:2000-10-01 00:00:00

  • 4-Hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (Tempol) inhibits peroxynitrite-mediated phenol nitration.

    abstract::Peroxynitrite (PN), a very reactive oxidant formed by the combination of superoxide and nitric oxide, appears to play a role in producing tissue damage in a number of inflammatory conditions. Pharmacological scavenging and decomposition of PN within these areas has therapeutic value in several tissue injury models. Re...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章

    doi:10.1021/tx990159t

    authors: Carroll RT,Galatsis P,Borosky S,Kopec KK,Kumar V,Althaus JS,Hall ED

    更新日期:2000-04-01 00:00:00

  • Role of metallothionein in zinc(II) and chromium(III) mediated tolerance to carbon tetrachloride hepatotoxicity: evidence against a trichloromethyl radical-scavenging mechanism.

    abstract::The .CCl3 radical generated during the metabolism of CCl4 is readily spin trapped in vivo and in vitro by phenyl N-tert-butylnitrone (PBN) to form the stable PBN/.CCl3 radical adduct, which can then be extracted into organic solvents and detected by ESR spectroscopy. We have used this technique to examine the proposed...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章

    doi:10.1021/tx00035a017

    authors: Hanna PM,Kadiiska MB,Jordan SJ,Mason RP

    更新日期:1993-09-01 00:00:00

  • Differential metabolism of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in mice humanized for CYP1A1 and CYP1A2.

    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

    authors: Cheung C,Ma X,Krausz KW,Kimura S,Feigenbaum L,Dalton TP,Nebert DW,Idle JR,Gonzalez FJ

    更新日期:2005-09-01 00:00:00

  • Enolate-Forming Compounds as a Novel Approach to Cytoprotection.

    abstract::Evidence from laboratory studies and clinical trials suggests that plant-derived polyphenolic compounds such as curcumin, resveratrol, or phloretin might be useful in the treatment of certain diseases (e.g., Alzheimer's disease) and acute tissue injury states (e.g., spinal cord trauma). However, despite this potential...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章,评审

    doi:10.1021/acs.chemrestox.6b00300

    authors: LoPachin RM,Geohagen BC,Nordstrøm LU,Gavin T

    更新日期:2016-12-19 00:00:00

  • Effects of intracerebroventricular administration of 5-(glutathion-S-yl)-alpha-methyldopamine on brain dopamine, serotonin, and norepinephrine concentrations in male Sprague-Dawley rats.

    abstract::alpha-Methyldopamine (alpha-MeDA) is a metabolite of the serotonergic neurotoxicants 3,4-(+/-)-(methylenedioxy)amphetamine (MDA) and 3,4-(+/-)-(methylenedioxy)methamphetamine (MDMA). alpha-MeDA readily oxidizes, and in the presence of glutathione (GSH) it forms 5-(glutathion-S-yl)-alpha-methyldopamine [5-(glutathion-S...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章

    doi:10.1021/tx9501546

    authors: Miller RT,Lau SS,Monks TJ

    更新日期:1996-03-01 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

    doi:10.1021/tx0498657

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

    更新日期:2004-09-01 00:00:00

  • Oxanosine Monophosphate Is a Covalent Inhibitor of Inosine 5'-Monophosphate Dehydrogenase.

    abstract::Reactive nitrogen species (RNS) are produced during infection and inflammation, and the effects of these agents on proteins, DNA, and lipids are well recognized. In contrast, the effects of RNS damaged metabolites are less appreciated. 5-Amino-3-β-(d-ribofuranosyl)-3 H-imidazo-[4,5- d][1,3]oxazine-7-one (oxanosine) an...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章

    doi:10.1021/acs.chemrestox.8b00342

    authors: Yu R,Kim Y,Maltseva N,Braunstein P,Joachimiak A,Hedstrom L

    更新日期:2019-03-18 00:00:00

  • Ethyl octylphosphonofluoridate and analogs: optimized inhibitors of neuropathy target esterase.

    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

    authors: Wu SY,Casida JE

    更新日期:1995-12-01 00:00:00

  • Oxidation of aflatoxins and sterigmatocystin by human liver microsomes: significance of aflatoxin Q1 as a detoxication product of aflatoxin B1.

    abstract::Aflatoxin Q1 8,9-oxide was synthesized and found to yield lower levels of N7-guanyl adducts than obtained from aflatoxin B1 8,9-oxide when mixed with calf thymus DNA or Salmonella typhimurium TA 98 cells. However, when S. typhimurium TA 98 was treated with the (analogous) epoxides of aflatoxin B1, aflatoxin G1, aflato...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章

    doi:10.1021/tx00026a009

    authors: Raney KD,Shimada T,Kim DH,Groopman JD,Harris TM,Guengerich FP

    更新日期:1992-03-01 00:00:00

  • Mechanism of reaction of beta-(aryloxy)acroleins with nucleosides.

    abstract::The mechanism of DNA adduct formation by acroleins substituted with good leaving groups in the beta-position was investigated using [3-2H]-3-(p-nitrophenoxy)acrolein (1). Reaction of 1 with guanosine at acidic pH produced 9-beta-D-ribofuranosylpyrimido[1,2-alpha]purin-10(3H)-one containing equal amounts of deuterium a...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章

    doi:10.1021/tx950105t

    authors: Reddy GR,Marnett LJ

    更新日期:1996-01-01 00:00:00

  • Polychlorinated Biphenyl Quinone Induces Caspase 1-Mediated Pyroptosis through Induction of Pro-inflammatory HMGB1-TLR4-NLRP3-GSDMD Signal Axis.

    abstract::Polychlorinated biphenyls (PCBs) are one of the most refractory environmental pollutants. Because of their ubiquitous existence in the biological systems (including human body), it is important to investigate their toxic behavior. Our previous findings demonstrated that a high reactive metabolite of PCB, namely PCB29-...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章

    doi:10.1021/acs.chemrestox.8b00376

    authors: Dong W,Zhu Q,Yang B,Qin Q,Wang Y,Xia X,Zhu X,Liu Z,Song E,Song Y

    更新日期:2019-06-17 00:00:00

  • N6-Formyllysine as a Biomarker of Formaldehyde Exposure: Formation and Loss of N6-Formyllysine in Nasal Epithelium in Long-Term, Low-Dose Inhalation Studies in Rats.

    abstract::Exposure to both endogenous and exogenous formaldehyde has been established to be carcinogenic, likely by virtue of forming nucleic acid and proteins adducts such as N6-formyllysine. To better assess N6-formyllysine as a biomarker of formaldehyde exposure, we studied accumulation of N6-formyllysine adducts in tissues ...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章

    doi:10.1021/acs.chemrestox.7b00075

    authors: Edrissi B,Taghizadeh K,Moeller BC,Yu R,Kracko D,Doyle-Eisele M,Swenberg JA,Dedon PC

    更新日期:2017-08-21 00:00:00

  • Determination and metabolism of dithiol chelating agents: the zinc chelate of the dimethyl ester of meso-2,3-dimercaptosuccinic acid increase biliary excretion of cadmium and platinum.

    abstract::meso-2,3-Dimercaptosuccinic acid is an orally active chelating agent useful for the treatment of lead intoxication. Since it is believed to be extracellular in its distribution, analogs have been synthesized in a search for one that will enter the cell and successfully complete for firmly bound intracellular toxic hea...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章

    doi:10.1021/tx00032a010

    authors: Aposhian HV,Levine DJ,Rivera M,Fernando Q

    更新日期:1993-03-01 00:00:00

  • Role of cytochrome P450 enzyme induction in the metabolic activation of benzo[c]phenanthrene in human cell lines and mouse epidermis.

    abstract::The environmental contaminant benzo[c]phenanthrene (B[c]Ph) has weak carcinogenic activity in rodent bioassays; however, the fjord region diol epoxides of B[c]Ph, B[c]Ph-3,4-diol 1,2-epoxides (B[c]PhDE), are potent carcinogens. To determine the role of cytochrome P450 isozymes in the activation of B[c]Ph in MCF-7 cell...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章

    doi:10.1021/tx960174n

    authors: Einolf HJ,Story WT,Marcus CB,Larsen MC,Jefcoate CR,Greenlee WF,Yagi H,Jerina DM,Amin S,Park SS,Gelboin HV,Baird WM

    更新日期:1997-05-01 00:00:00

  • Notopterygium forbesii boiss extract and its active constituents increase reactive species and heme oxygenase-1 in human fetal hepatocytes: mechanisms of action.

    abstract::Notopterygium forbesii Boiss (NF) has been used as a traditional Chinese medicine for the treatment of common cold and rheumatism. However, there has been limited research on the biological properties of NF, and the mechanisms of action remain unknown. Here, we aimed to study the mechanism of NF-induced heme oxygenase...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章

    doi:10.1021/tx800301f

    authors: Tang SY,Wang H,Zhang W,Halliwell B

    更新日期:2008-12-01 00:00:00

  • Studies on the adduct heterogeneity of benzo[a]pyrene 7, 8-dihydrodiol 9,10-epoxide stereoisomers covalently bound to deoxyribooligonucleotides by induced circular dichroism and light absorption spectroscopy.

    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

    authors: Pradhan P,Jernström B,Seidel A,Nordén B,Gräslund A

    更新日期:1999-05-01 00:00:00

  • Gut microbiome perturbations induced by bacterial infection affect arsenic biotransformation.

    abstract::Exposure to arsenic affects large human populations worldwide and has been associated with a long list of human diseases, including skin, bladder, lung, and liver cancers, diabetes, and cardiovascular disorders. In addition, there are large individual differences in susceptibility to arsenic-induced diseases, which ar...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章

    doi:10.1021/tx4002868

    authors: Lu K,Cable PH,Abo RP,Ru H,Graffam ME,Schlieper KA,Parry NM,Levine S,Bodnar WM,Wishnok JS,Styblo M,Swenberg JA,Fox JG,Tannenbaum SR

    更新日期:2013-12-16 00:00:00

  • Characterization of benzo[a]pyrene anti-diol epoxide adducts to human histones.

    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

    authors: SooHoo CK,Singh K,Skipper PL,Tannenbaum SR,Dasari RR

    更新日期:1994-03-01 00:00:00

  • Use of electrochemical oxidation and model peptides to study nucleophilic biological targets of reactive metabolites: the case of rimonabant.

    abstract::Electrochemical oxidation of drug molecules is a useful tool to generate several different types of metabolites. In the present study we developed a model system involving electrochemical oxidation followed by characterization of the oxidation products and their propensity to modify peptides. The CB1 antagonist rimona...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章

    doi:10.1021/tx500255r

    authors: Thorsell A,Isin EM,Jurva U

    更新日期:2014-10-20 00:00:00

  • Subchronic toxicity and cardiovascular responses in spontaneously hypertensive rats after exposure to multiwalled carbon nanotubes by intratracheal instillation.

    abstract::The tremendous demand of the market for carbon nanotubes has led to their massive production that presents an increasing risk through occupational exposure. Lung deposition of carbon nanotubes is known to cause acute localized pulmonary adverse effects. However, systemic cardiovascular damages associated with acute pu...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章

    doi:10.1021/tx5004003

    authors: Chen R,Zhang L,Ge C,Tseng MT,Bai R,Qu Y,Beer C,Autrup H,Chen C

    更新日期:2015-03-16 00:00:00

  • Model system to study the influence of aggregation on the hemolytic potential of silica nanoparticles.

    abstract::A well-defined silica nanoparticle model system was developed to study the effect of the size and structure of aggregates on their membranolytic activity. The aggregates were stable and characterized using transmission electron microscopy, dynamic light scattering, nitrogen adsorption, small-angle X-ray scattering, in...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章

    doi:10.1021/tx2002178

    authors: Thomassen LC,Rabolli V,Masschaele K,Alberto G,Tomatis M,Ghiazza M,Turci F,Breynaert E,Martra G,Kirschhock CE,Martens JA,Lison D,Fubini B

    更新日期:2011-11-21 00:00:00

  • Oxidation of N-hydroxynorzimeldine to a stable nitrone by hepatic monooxygenases.

    abstract::Liver microsomes from uninduced hogs catalyzed the NADPH-dependent N-oxidation of the hydroxylamine (Z)-3-(4-bromophenyl)-N-hydroxy-N-methyl-3-(3-pyridyl)allylamine. The conjugated nitrone N-[(2Z)-3-(4-bromophenyl)-3-(3-pyridyl)-2-propenylidene]methylamin e N-oxide was the principal product and accounted for 90-95% of...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章

    doi:10.1021/tx00017a007

    authors: Cashman JR,Yang ZC,Högberg T

    更新日期:1990-09-01 00:00:00

  • Reactive sulfur species: kinetics and mechanism of the hydrolysis of cysteine thiosulfinate ester.

    abstract::The kinetics and mechanisms of the hydrolysis of cysteine thiosulfinate ester (CyS(O)SCy ( x- ), x = 0-2) have been investigated by stopped-flow spectrophotometry between pH 6 and pH 14. The rate-limiting reaction of hydroxide is observed for pH < 13. More complicated kinetics are observed above pH 13, where the hydro...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章

    doi:10.1021/tx700168z

    authors: Nagy P,Ashby MT

    更新日期:2007-09-01 00:00:00

  • Development of a partition-controlled dosing system for cell assays.

    abstract::Hydrophobic and volatile chemicals have proven to be difficult to dose in cell assays. Cosolvents are often needed to dissolve these chemicals in cell culture medium. Moreover, the free concentration of these chemicals in culture medium may diminish over time due to metabolism, evaporation, and nonspecific binding to ...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章

    doi:10.1021/tx1002595

    authors: Kramer NI,Busser FJ,Oosterwijk MT,Schirmer K,Escher BI,Hermens JL

    更新日期:2010-11-15 00:00:00

  • Catalytic activities of human alpha class glutathione transferases toward carcinogenic dibenzo[a,l]pyrene diol epoxides.

    abstract::In this study, human glutathione transferases (GSTs) of alpha class have been assayed with the ultimate carcinogenic (-)-anti- and (+)-syn-diol epoxides (DEs) derived from the nonplanar dibenzo[a,l]pyrene (DBPDE) and the (+)-anti-diol epoxide of the planar benzo[a]pyrene [(+)-anti-BPDE] in the presence of glutathione ...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章

    doi:10.1021/tx025519i

    authors: Dreij K,Sundberg K,Johansson AS,Nordling E,Seidel A,Persson B,Mannervik B,Jernström B

    更新日期:2002-06-01 00:00:00

  • Harmful and beneficial effects of organic monosulfides, disulfides, and polysulfides in animals and humans.

    abstract::Many organic sulfides (mono-, di-, and polysulfides) are present in our environment. Simple derivatives are produced by some plants and animals, while complex sulfides are secondary metabolites of several genera of bacteria and fungi. Sulfides play an important role in the smell and taste of food, and many such compou...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章,评审

    doi:10.1021/tx200373u

    authors: Munday R

    更新日期:2012-01-13 00:00:00

  • Serum metabolomics reveals irreversible inhibition of fatty acid beta-oxidation through the suppression of PPARalpha activation as a contributing mechanism of acetaminophen-induced hepatotoxicity.

    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

    authors: Chen C,Krausz KW,Shah YM,Idle JR,Gonzalez FJ

    更新日期:2009-04-01 00:00:00

  • Up-Regulation of T-Cell Activation MicroRNAs in Drug-Specific CD4+ T-Cells from Hypersensitive Patients.

    abstract::Dysregulation in the expression of microRNAs (miRNAs), single-stranded RNAs which regulate gene expression, has been associated with diseases such as Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), although their cellular origin has not been explored. Thus, the focus of this work was to study expressi...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章

    doi:10.1021/acs.chemrestox.7b00330

    authors: Monroy-Arreola A,Durán-Figueroa NV,Méndez-Flores S,Domínguez-Cherit J,Watkinson J,Badillo-Corona JA,Whitaker P,Naisbitt DJ,Castrejón-Flores JL

    更新日期:2018-06-18 00:00:00

  • Tobacco-specific nitrosamine-derived O2-alkylthymidines are potent mutagenic lesions in SOS-induced Escherichia coli.

    abstract::To investigate the biological effects of the O(2)-alkylthymidines induced by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), we have replicated a plasmid containing O(2)-methylthymidine (O(2)-Me-dT) or O(2)-[4-(3-pyridyl-4-oxobut-1-yl]thymidine (O(2)-POB-dT) in Escherichia coli w...

    journal_title:Chemical research in toxicology

    pub_type: 杂志文章

    doi:10.1021/tx200435d

    authors: Jasti VP,Spratt TE,Basu AK

    更新日期:2011-11-21 00:00:00