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1.
Arch Toxicol ; 98(4): 1111-1123, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38368582

RESUMO

While grouping/read-across is widely used to fill data gaps, chemical registration dossiers are often rejected due to weak category justifications based on structural similarity only. Metabolomics provides a route to robust chemical categories via evidence of shared molecular effects across source and target substances. To gain international acceptance, this approach must demonstrate high reliability, and best-practice guidance is required. The MetAbolomics ring Trial for CHemical groupING (MATCHING), comprising six industrial, government and academic ring-trial partners, evaluated inter-laboratory reproducibility and worked towards best-practice. An independent team selected eight substances (WY-14643, 4-chloro-3-nitroaniline, 17α-methyl-testosterone, trenbolone, aniline, dichlorprop-p, 2-chloroaniline, fenofibrate); ring-trial partners were blinded to their identities and modes-of-action. Plasma samples were derived from 28-day rat tests (two doses per substance), aliquoted, and distributed to partners. Each partner applied their preferred liquid chromatography-mass spectrometry (LC-MS) metabolomics workflows to acquire, process, quality assess, statistically analyze and report their grouping results to the European Chemicals Agency, to ensure the blinding conditions of the ring trial. Five of six partners, whose metabolomics datasets passed quality control, correctly identified the grouping of eight test substances into three categories, for both male and female rats. Strikingly, this was achieved even though a range of metabolomics approaches were used. Through assessing intrastudy quality-control samples, the sixth partner observed high technical variation and was unable to group the substances. By comparing workflows, we conclude that some heterogeneity in metabolomics methods is not detrimental to consistent grouping, and that assessing data quality prior to grouping is essential. We recommend development of international guidance for quality-control acceptance criteria. This study demonstrates the reliability of metabolomics for chemical grouping and works towards best-practice.


Assuntos
Espectrometria de Massa com Cromatografia Líquida , Metabolômica , Ratos , Masculino , Feminino , Animais , Reprodutibilidade dos Testes , Metabolômica/métodos , Fluxo de Trabalho
2.
Inorg Chem ; 60(6): 3749-3760, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33647206

RESUMO

Two monoclinic polymorphs of [Ag(NH3)2]MnO4 containing a unique coordination mode of permanganate ions were prepared, and the high-temperature polymorph was used as a precursor to synthesize pure AgMnO2. The hydrogen bonds between the permanganate ions and the hydrogen atoms of ammonia were detected by IR spectroscopy and single-crystal X-ray diffraction. Under thermal decomposition, these hydrogen bonds induced a solid-phase quasi-intramolecular redox reaction between the [Ag(NH3)2]+ cation and MnO4- anion even before losing the ammonia ligand or permanganate oxygen atom. The polymorphs decomposed into finely dispersed elementary silver, amorphous MnOx compounds, and H2O, N2 and NO gases. Annealing the primary decomposition product at 573 K, the metallic silver reacted with the manganese oxides and resulted in the formation of amorphous silver manganese oxides, which started to crystallize only at 773 K and completely transformed into AgMnO2 at 873 K.

3.
Toxicol Lett ; 382: 13-21, 2023 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-37164126

RESUMO

In long term rodent studies administering Cyclobutrifluram (TYMIRIUM® Technology), a new agrochemical, there was a slight elevation of incidence of hepatocellular carcinomas in male CD-1 mice that was within the historical control range but appeared to be dose responsive. Cyclobutrifluram's ability to activate mouse constitutive androstane receptor (CAR) mediated gene transcription was confirmed in vitro, therefore a 28-day dietary toxicity study was conducted in vivo in male CD-1 mice to assess the CAR activation mode of action hypothesis of Cyclobutrifluram along with phenobarbital, a known CAR activator. In addition to other end points comprehensive (polar and lipidomic) hybrid metabolomics analyses were performed on terminal plasma and liver samples following 2-, 7- and 28-days dietary exposure to cyclobutrifluram and phenobarbital. The data generation and quality assessments were performed in line with the principles of the MEtabolomics standaRds Initiative in Toxicology (MERIT).First the full annotated feature set was used to compare the metabolomic changes induced by the administration of the two test substances using Shared and Unique Structures plots. This gave a comprehensive overview of the similarity of the two effect profiles showing good correlation and demonstrated that no other, alternative effect signatures were detected. Then the phenobarbital induced differentially abundant metabolites were selected, compared to the literature and their direction of change was assessed in cyclobutrifluram profiles, finding good agreement. Both approaches concluded that the metabolomics data supports the CAR activation hypothesis. Comparison of the metabolomic effect profiles can be a line of evidence in mode of action hypothesis testing in the chemical risk assessment process.


Assuntos
Segurança Química , Neoplasias Hepáticas , Masculino , Camundongos , Animais , Fígado/metabolismo , Hepatócitos , Receptores Citoplasmáticos e Nucleares/metabolismo , Fenobarbital/toxicidade , Fenobarbital/metabolismo , Neoplasias Hepáticas/patologia , Metabolômica
4.
Science ; 194(4265): 627-30, 1976 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-136041

RESUMO

Two unwanted contaminants, 3,4,3',4'-tetrachloroazoxybenzene (TCAOB) and 3,4,3',4'-tetrachloroazobenzene (TCAB), formed in the commercial synthesis of 3,4-dichloroaniline or of herbicides made from 3,4-dichloroaniline, were responsible for three outbreaks of acne among chemical workers. TCAOB and TCAB are approximately isosteric to 2,3,7,8-tetrachlorodibenzo-p-dioxin and 2,3,7,8-tetrachlorodibenzofuran, two well-known contaminants that cause acne. All four of these agents are potent inducers of hepatic aryl hydrocarbon hydroxylase activity and compete for stereospecific binding sites in the hepatic cytosol, which are thought to be the receptor sites for the induction of this enzyme. Among the chlorinated azoxy and azobenzenes, the potency of a congener to induce aryl hydrocarbon hydroxylase activity correlates with its binding affinity for the hepatic cytosol specific binding sites and its capacity to induce acne; this relation between structure and activity parallels that observed for the chlorinated dibenzo-p-dioxins and dibenzofurans.


Assuntos
Acne Vulgar/induzido quimicamente , Hidrocarboneto de Aril Hidroxilases/biossíntese , Compostos Azo/farmacologia , Clorobenzenos/farmacologia , Dermatite Ocupacional/induzido quimicamente , Animais , Compostos Azo/metabolismo , Sítios de Ligação , Ligação Competitiva , Clorobenzenos/metabolismo , Citosol/metabolismo , Indução Enzimática/efeitos dos fármacos , Herbicidas/síntese química , Humanos , Fígado/enzimologia , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Dibenzodioxinas Policloradas/farmacologia , Relação Estrutura-Atividade
5.
Cancer Res ; 51(24): 6568-73, 1991 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-1742729

RESUMO

The antileukemic activity of L-asparaginase (ASNase), an important component of therapy for acute lymphoblastic leukemia, is thought to result from depletion of serum L-asparagine (Asn). In studies of the pharmacological effects of ASNase, investigators have reported prolonged reduction in the serum concentration of Asn after the administration of ASNase. Such measurements may not be valid because ASNase present in the blood sample may hydrolyze Asn before its determination. We examined recovery of [U-14C]Asn from blood samples with and without various concentrations of added ASNase. In the presence of greater than or equal to 0.01 IU/ml of ASNase, the amount of [U-14C]Asn recovered was less than 15% of that without ASNase. Utilizing this assay, we studied the effect of 2 known inhibitors of ASNase in an attempt to improve Asn recovery. In the presence of aspartic beta semialdehyde (ASA), or 5-diazo-4-oxo-L-norvaline (DONV), and up to 1.0 IU/ml ASNase, Asn levels remained at greater than 90% of control. ASA prevented the hydrolysis of exogenous Asn in blood samples drawn from patients after ASNase injection. We also developed a method to determine Asn in serum utilizing high pressure liquid chromatography. Using this method, we found that the Asn level was greater than 90% of a normal level in the presence of 40 mM DONV and 1.0 IU/ml ASNase. Examination of serum from 4 patients treated with ASNase showed that Asn is detectable 7-19 days sooner when DONV is present in the blood collection system than in its absence. We conclude that: (a) as little as 0.01 IU/ml ASNase can hydrolyze Asn added to blood; (b) continued hydrolysis of Asn by ASNase ex vivo can result in falsely low serum Asn measurements; (c) ASA or DONV present in the collection tubes obviates the problem of continued ASNase activity; and (d) the degree and duration of Asn depletion after ASNase therapy is much less than previously believed. Thus, for accurate measurements of the duration and degree of Asn depletion by ASNase, an ASNase inhibitor such as ASA or DONV should be present in the blood collection system.


Assuntos
Asparaginase/antagonistas & inibidores , Asparagina/sangue , Ácido Aminolevulínico/análogos & derivados , Ácido Aminolevulínico/farmacologia , Asparaginase/farmacologia , Asparaginase/uso terapêutico , Ácido Aspártico/análogos & derivados , Ácido Aspártico/sangue , Ácido Aspártico/farmacologia , Ácido Aspártico/uso terapêutico , Cromatografia Líquida de Alta Pressão , Humanos
6.
Int J Radiat Oncol Biol Phys ; 10(9): 1609-13, 1984 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-6548210

RESUMO

Nitro-compounds containing an acetylated acetohydroxamic acid side chain in the N-1 position of a 5-membered ring nitrogen heterocycle have been synthesized. These compounds, which can generate isocyanates via a Lossen rearrangement, were evaluated in order to test the hypothesis that they may be effective radiation and chemosensitizing agents by nature of their isocyanate-associated carbamoylating potential. Evaluation of one such compound, DJW-77 (1(O-Acetyl-Acetohydroxamic acid)-3-nitropyrazole) as a radiation sensitizer, chemosensitizer and hypoxic cell toxin is reported. In vitro DJW-77 demonstrates a potent selective cytotoxicity toward hypoxic EMT-6 tumor cells, is an effective potentiator of CCNU toxicity and is comparable to MISO with respect to its radiation-sensitizing potential. The activity of the drug is eliminated under aerobic conditions. To test the hypothesis that the activity of DJW-77 is related to isocyanate generation, the non-acetylated analog of DJW-77 (which does not directly undergo the Lossen rearrangement) and the parent 3-nitropyrazole ring structure were evaluated. Neither compound enhanced CCNU toxicity, and on an equimolar basis were inferior to DJW-77 as radiation sensitizers. While the non-acetylated analog was cytotoxic to hypoxic cells, relative to DJW-77 this activity was substantially reduced. These studies indicate that the addition of a side chain capable of generating an isocyanate can enhance the cytotoxicity and sensitizing activity of nitroheterocycles.


Assuntos
Antineoplásicos/farmacologia , Oxigênio/fisiologia , Pirazóis/farmacologia , Radiossensibilizantes/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Relação Dose-Resposta a Droga , Relação Dose-Resposta à Radiação , Sinergismo Farmacológico , Lomustina/farmacologia , Neoplasias Experimentais/patologia
7.
J Med Chem ; 44(24): 4157-69, 2001 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-11708917

RESUMO

A series of novel C(1) alkylphosphinic acid analogues of the prostaglandin-F family have been evaluated at the eight human prostaglandin receptors for potential use in the treatment of osteoporosis. Using molecular modeling as a tool for structure-based drug design, we have discovered that the phosphinic acid moiety (P(O)(OH)R) behaves as an isostere for the C(1) carboxylic acid in the human prostaglandin FP binding assay in vitro and possesses enhanced hFP receptor selectivity when compared to the parent carboxylic acid. When evaluated in vivo, the methyl phosphinic acid analogue (4b) produced a bone anabolic response in rats, returning bone mineral volume (BMV) [corrected], to intact levels in the distal femur in the ovariectomized rat (OVX) model. These results suggest that prostaglandins of this class may be useful agents in the treatment of diseases associated with bone loss.


Assuntos
Osso e Ossos/efeitos dos fármacos , Dinoprosta/síntese química , Ácidos Fosfínicos/síntese química , Prostaglandinas F Sintéticas/síntese química , Absorciometria de Fóton , Sequência de Aminoácidos , Animais , Ligação Competitiva , Densidade Óssea/efeitos dos fármacos , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/metabolismo , Células COS , Dinoprosta/análogos & derivados , Dinoprosta/química , Dinoprosta/metabolismo , Dinoprosta/farmacologia , Feminino , Humanos , Modelos Moleculares , Dados de Sequência Molecular , Osteoporose/tratamento farmacológico , Ovariectomia , Ácidos Fosfínicos/química , Ácidos Fosfínicos/metabolismo , Ácidos Fosfínicos/farmacologia , Prostaglandinas F Sintéticas/química , Prostaglandinas F Sintéticas/metabolismo , Prostaglandinas F Sintéticas/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptores de Prostaglandina/metabolismo , Relação Estrutura-Atividade , Tomografia Computadorizada por Raios X , Transfecção
8.
Biochem Pharmacol ; 52(11): 1787-803, 1996 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-8986142

RESUMO

A number of studies have examined the structure-activity relationships for the agonist activity of Ah receptor (AhR) ligands. Fewer studies have considered the structural basis for potential antagonist properties. Certain ellipticine derivatives have been reported to bind to the AhR and inhibit the ability of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to transform the AhR to a form that recognizes a dioxin-responsive enhancer element (DRE) upstream of the cytochrome P4501A1 gene. In the present study, over 30 ellipticine derivatives and structurally related compounds were examined for their ability to bind to the AhR, activate it to a DRE-binding form, induce the luciferase gene under control of a DRE-containing enhancer, and block activation of the AhR by TCDD. The ability of several ellipticine derivatives to inhibit TCDD-elicited DRE binding and TCDD-induced luciferase activity was inversely related to their ability to alone stimulate these responses. The most potent antagonist activity was related to good AhR binding characteristics in terms of conforming to previously predicted 14 x 12 x 5 A van der Waals dimensions and the presence of an electron-rich ring nitrogen at or near a relatively unsubstituted X-axis terminal position. Based on these data, a number of flavone derivatives were synthesized and tested for their relative agonist/antagonist activity. These additional data were consistent with the hypothesis that an electron-rich center near or along a lateral position of the van der Waals binding cavity is a characteristic that enhances AhR antagonist activity.


Assuntos
Elipticinas/farmacologia , Flavonoides/farmacologia , Receptores de Hidrocarboneto Arílico/antagonistas & inibidores , Animais , DNA/metabolismo , Elementos Facilitadores Genéticos , Masculino , Dibenzodioxinas Policloradas/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Hidrocarboneto Arílico/agonistas , Relação Estrutura-Atividade
9.
Biochem Pharmacol ; 47(11): 1965-7, 1994 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-8010981

RESUMO

A newly synthesized affinity ligand, (R,S)-5-isothiocyanonicotine (ISCN-N) was found to inhibit irreversibly the binding of [3H]methylcarbamylcholine (a specific nicotinic receptor ligand) to brain membranes. Plots of percent inhibition versus ligand concentration yielded an IC50 of 7 x 10(-8) M for SCN-N and Ki values of 6 x 10(-9) and 2 x 10(-9) M for (R,S)-5-aminonicotine and (S)-nicotine, respectively. The IC50 value for irreversible inhibition of [3H]methylcarbamylcholine by SCN-N was 2 x 10(-7) M. The affinity ligand irreversibly inhibited brain nicotinic receptors in vivo in a dose-dependent manner, the inhibition being 49% at a dose of 20 mumol/kg. Behavioral studies in mice revealed that SCN-N had less than one-fifth the potency of nicotine in producing muscle weakness and seizures, whereas 5-aminonicotine was without significant behavioral effects at doses up to 20 mumol/kg.


Assuntos
Encéfalo/efeitos dos fármacos , Nicotina/análogos & derivados , Antagonistas Nicotínicos , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Carbacol/análogos & derivados , Carbacol/metabolismo , Bovinos , Locomoção/efeitos dos fármacos , Camundongos , Nicotina/antagonistas & inibidores , Nicotina/síntese química , Nicotina/farmacologia , Nicotina/toxicidade
10.
Radiat Res ; 105(3): 296-306, 1986 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-3961096

RESUMO

A series of acetohydroxamic acid derivatives of 3-nitropyrazole were synthesized and evaluated as radiation sensitizing agents in vitro to test the hypothesis that any increase in sensitizing efficiency over that predicted from electron affinity considerations would be proportional to the rate of isocyanate (R--N = C = O) liberation subsequent to a Lossen rearrangement. EMT-6/Ro cells were exposed to the drugs for 1 h prior to irradiation under aerobic and hypoxic conditions. Sensitizer enhancement ratios (SER) were determined for each compound, and corresponding C1.6 values were plotted as a function of reduction potential (E 1/2). Substitution of acetohydroxamates at the N-1 position of the parent nitropyrazole produced a series of compounds with sensitizing potentials exceeding (9- to 50-fold) those predicted based on their electron affinities. While the current studies do not rule out isocyanate involvement in the enhanced sensitization, they suggest that the enhanced sensitizing ability was not directly proportional to the rate of the Lossen rearrangement. The data suggest that the addition of an acetohydroxamic acid side chain can effectively enhance the sensitizing ability of electron-affinic compounds in excess of that associated with redox potential.


Assuntos
Pirazóis/farmacologia , Radiossensibilizantes/farmacologia , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Relação Dose-Resposta a Droga , Relação Dose-Resposta à Radiação , Técnicas In Vitro , Neoplasias Mamárias Experimentais/patologia , Camundongos , Pirazóis/síntese química , Radiossensibilizantes/síntese química , Relação Estrutura-Atividade
11.
Org Lett ; 3(16): 2505-8, 2001 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-11483046

RESUMO

[structure: see text] The total synthesis of the tetracyclic alkaloids stemonamide (1) and isostemonamide (2) is presented. The key step is the reaction between a silyloxyfuran and an N-acyliminium ion. The second quaternary center is created by an intramolecular aldol spirocyclization. After 1,4-addition of an appropriate side chain, the methyl and double bond are installed by Mannich reaction. The seven-membered ring is closed by intramolecular nucleophilic displacement.


Assuntos
Alcaloides/síntese química , Plantas/química , Compostos Policíclicos/síntese química , Compostos de Espiro/síntese química , Cristalografia por Raios X , Ciclização , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Raízes de Plantas/química , Espectrofotometria Infravermelho
12.
Life Sci ; 60(15): 1271-7, 1997.
Artigo em Inglês | MEDLINE | ID: mdl-9096244

RESUMO

A study was undertaken to assess the receptor binding characteristics of [3H]4-benzylpempidine to an allosteric site on calf brain membranes associated with nicotinic cholinergic receptors and to compare the binding affinity of novel arylpempidine analogs with their ability to antagonize the behavioral effects of nicotine in mice. Scatchard analysis of the binding yielded a K(d) of 20 nM and a B(max) of 330 fmols/mg membrane protein. [3H]4-benzylpempidine appears to be a more satisfactory ligand than [3H]mecamylamine, since it possessed a 50-fold greater affinity and its binding was far less sensitive to inorganic ions and Tris. Among the arylpempidine analogs 4-m-chlorobenzylidenepempidine and 4-benzylidenepempidine had the lowest K(i) values (1.4 nM and 5.0 nM, respectively) and were the most potent in antagonizing nicotine-induced seizures in mice. Although the K(i) values for pempidine and mecamylamine were 1-2 orders of magnitude greater than any of the arylpempidines, the dose required to antagonize nicotine-induced seizures in mice was comparable to the arylpempidines. One explanation for this apparent discrepancy in the correlation of binding affinity and nicotine antagonism is the lower brain penetration of arylpempidines compared to mecamylamine, following their systemic administration to mice.


Assuntos
Encéfalo/metabolismo , Canais de Cálcio/metabolismo , Antagonistas Nicotínicos/metabolismo , Pempidina/metabolismo , Receptores Nicotínicos/metabolismo , Animais , Ligação Competitiva , Cálcio/metabolismo , Bovinos , Membrana Celular/metabolismo , Ligantes , Mecamilamina/metabolismo , Camundongos , Nicotina/antagonistas & inibidores , Nicotina/farmacologia , Pempidina/análogos & derivados , Pempidina/farmacologia , Convulsões/induzido quimicamente , Convulsões/prevenção & controle
13.
Food Chem Toxicol ; 24(6-7): 781-7, 1986.
Artigo em Inglês | MEDLINE | ID: mdl-3023216

RESUMO

A series of halodibenzo-p-dioxins bearing the arylazide photolabile functional group were synthesized and tested as photoaffinity labels for the Ah receptor. 2-Azido-3-iodo-7,8-dibromodibenzo-p-dioxin (KD = 0.76 X 10(-9) M) was selected for radiosynthesis. Analysis of the 125I-photoaffinity-labelled proteins in mouse-liver cytosol by denaturing gel electrophoresis revealed two peptides which had apparent molecular masses of 95,000 and 70,000 daltons respectively, were labelled in an approximately 1:1 ratio and were selectively labelled at low concentrations of the photoaffinity ligand (0.05 KD = 0.04 X 10(-9) M). In addition, their labelling was inhibited by co-incubation with an excess of unlabelled ligand. On chromatographic separation under non-denaturing conditions, these two peptides co-migrated. These studies suggest that the Ah receptor in mouse liver cytosol is a heterodimer composed of two non-covalently bound peptides (95 K and 70 K) which each have a ligand binding site.


Assuntos
Marcadores de Afinidade/metabolismo , Receptores de Droga/análise , Animais , Citosol/metabolismo , Técnicas In Vitro , Radioisótopos do Iodo , Camundongos , Camundongos Endogâmicos C57BL , Peso Molecular , Fotoquímica , Dibenzodioxinas Policloradas/metabolismo , Receptores de Hidrocarboneto Arílico , Receptores de Droga/metabolismo , Relação Estrutura-Atividade , Trítio
18.
Diabetologia ; 51(11): 2108-16, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18726085

RESUMO

AIMS/HYPOTHESIS: Troglitazone was approved for treatment of type 2 diabetes mellitus, but by 2000 it had been removed from all world markets due to severe drug-induced liver injury. Even today, we still do not know how many patients sustained a long-term liver injury. No system is in place to acquire that knowledge. Regarding toxicity mechanisms, controversy persists as to which ones are class effects of thiazolidinediones (TZDs) and which are unique to troglitazone. This study aims to provide long-term outcome data and new insights on mechanisms of troglitazone-induced liver injury. METHODS: This case series reports the liver injuries sustained by eleven type 2 diabetic patients treated with troglitazone between 1997 and 2000. Exhaustive review of medical records was performed for all patients. Long-term outcomes were available for all the non-fatal cases. A comprehensive literature review was also performed. RESULTS: Long-term liver injury progressing to cirrhosis was identified in seven patients. All eleven cases had liver injury patterns consistent with troglitazone toxicity. Analysis of these cases and of the experimental troglitazone toxicity data points to mitochondrial toxicity as a central factor. The general clinical patterns of mitochondrial hepatotoxic events are reviewed, as are the implications for other members of the TZD family. CONCLUSIONS/INTERPRETATION: This analysis enables the liver injury induced by troglitazone to be better understood. In future cases of delayed drug-induced liver injury that progresses after discontinuation, the possibility of mitochondrial toxicity should be considered. When appropriate, this can then be evaluated experimentally. Such proactive investigation may anticipate clinical risk before a large-scale therapeutic misadventure occurs. Drug-induced liver injury due to mitochondrial hepatotoxins may be less unpredictable than has previously been surmised.


Assuntos
Cromanos/efeitos adversos , Hipoglicemiantes/efeitos adversos , Falência Hepática/induzido quimicamente , Fígado/patologia , Mitocôndrias Hepáticas/patologia , Tiazolidinedionas/efeitos adversos , Adulto , Idoso , Biópsia , Feminino , Humanos , Fígado/efeitos dos fármacos , Fígado/fisiopatologia , Masculino , Pessoa de Meia-Idade , Mitocôndrias Hepáticas/efeitos dos fármacos , Mitocôndrias Hepáticas/fisiologia , Troglitazona
19.
Arch Biochem Biophys ; 450(1): 67-77, 2006 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-16545771

RESUMO

The aryl hydrocarbon receptor (AhR) is best known as a mediator of toxicity of a diverse family of xenobiotic chemicals such as dioxins and PCBs. However, many naturally occurring compounds also activate AhR. One such compound, 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), was isolated from tissue and found to be potent in preliminary tests [J. Song, M. Clagett-Dame, R.E. Peterson, M.E. Hahn, W.M. Westler, R.R. Sicinski, H.F. DeLuca, Proc. Natl. Acad. Sci. USA 99 (2002) 14694-14699]. We have synthesized ITE and [(3)H]ITE and further evaluated its AhR activity in several in vitro and in vivo assays in comparison with the toxic ligand, TCDD. AhR in Hepa1c1c7 cell cytosol bound [(3)H]ITE with high affinity and the AhR.ITE complex formed in vitro bound dioxin response element (DRE) oligonucleotide as potently as TCDD.AhR. In cells treated with ITE, nuclear translocation of AhR, and induction of CYP1A1 protein and of a DRE-dependent luciferase reporter gene were observed. ITE administered to pregnant DRE-LacZ transgenic mice activated fetal AhR, observed as X-gal staining in the same sites as in TCDD-treated mice. However, unlike TCDD, ITE did not induce cleft palate or hydronephrosis. TCDD but not ITE induced thymic atrophy in young adult mice, but both ITE and TCDD caused similar loss of cells and alterations of cell profiles in cultured fetal thymi. These data demonstrate that ITE is a potent AhR agonist in cell extracts, cultured cells, and intact animals, but does not cause the toxicity associated with the more stable xenobiotic ligand, TCDD.


Assuntos
Núcleo Celular/metabolismo , Dibenzodioxinas Policloradas/análogos & derivados , Propionatos/administração & dosagem , Pirazinas/administração & dosagem , Receptores de Hidrocarboneto Arílico/agonistas , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Animais , Atrofia/induzido quimicamente , Atrofia/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Linhagem Celular Tumoral , Sistema Livre de Células , Citocromo P-450 CYP1A1/biossíntese , Citocromo P-450 CYP1A1/genética , Dioxinas/metabolismo , Dioxinas/toxicidade , Feminino , Feto/anormalidades , Feto/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Ligantes , Camundongos , Camundongos Transgênicos , Bifenilos Policlorados/metabolismo , Bifenilos Policlorados/toxicidade , Dibenzodioxinas Policloradas/administração & dosagem , Dibenzodioxinas Policloradas/metabolismo , Dibenzodioxinas Policloradas/toxicidade , Gravidez , Propionatos/metabolismo , Propionatos/toxicidade , Ligação Proteica , Pirazinas/metabolismo , Pirazinas/toxicidade , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Timo/anormalidades , Timo/metabolismo , Timo/patologia , Xenobióticos/metabolismo , Xenobióticos/toxicidade
20.
Fed Proc ; 35(12): 2404-11, 1976 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-134910

RESUMO

The chlorinated dibenzo-p-dioxins and dibenzofurans are formed as trace contaminants during the synthesis of a number of commercially important chemicals. The prototype compound of this group, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), is one of the most potent low molecular weight toxins and teratogens known, and its inadvertent dispersion in the environment has caused concern about the potential hazard to human health. In studying the biochemical effects of TCDD, it was found to be extraordinarily potent as an inducer of two hepatic enzymes: 1) delta-aminolevulinic acid synthetase, the initial and rate-limiting enzyme in heme synthesis, and 2) aryl hydrocarbon hydroxylase, a cytochrome P-450-mediated microsomal monooxygenase. Among a series of halogenated dibenzo-p-dioxins there is an excellent correlation between their toxic potency and their potency as inducers of these two enzymes. The administration of polycyclic aromatic hydrocarbons (e.g., 3-methylcholanthrene (MC)) to certain inbred strains of mice induces aryl hydrocarbon hydroxylase, while other inbred strains fail to respond; and the trait of aryl hydrocarbon responsiveness is inherited as an autosomal dominant. TCDD, about 30,000 times as potent as MC, induces all strains whether responsive or nonresponsive to MC; however, the responsive strains are more sensitive (ED 50 approximately 1 X 10(-9) mole/kg) to TCDD than are the nonresponsive strains (ED50 larger than or equal to 1 X 10(-8) mole/kg). The results suggest that the mutation in the nonresponsive strains results in a ligand binding site (an induction receptor) that has a diminished affinity for MC and TCDD. The correlation among the halogenated dibenzo-p-dioxins, between their potency as toxins and their potency as inducers of aryl hydrocarbon hydroxylase, is discussed in relationship to various proposed mechanisms of toxicity.


Assuntos
Dioxinas/intoxicação , Resíduos Industriais , Dibenzodioxinas Policloradas/intoxicação , 5-Aminolevulinato Sintetase/metabolismo , Acne Vulgar/induzido quimicamente , Marcadores de Afinidade , Animais , Hidrocarboneto de Aril Hidroxilases/metabolismo , Embrião de Galinha , Galinhas , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Poluição Ambiental , Humanos , Cinética , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/metabolismo , Camundongos , Conformação Molecular , Dibenzodioxinas Policloradas/metabolismo , Dibenzodioxinas Policloradas/farmacologia , Teratogênicos
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