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1.
Chemosphere ; 240: 124970, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31726584

RESUMO

Measurement of specific biomarkers identified by proteomics provides a potential alternative method for risk assessment, which is required to discriminate between hepatotoxicity and endocrine disruption. In this study, adult zebrafish (Danio rerio) were exposed to the hepatotoxic substance acetaminophen (APAP) for 21 days, in a fish short-term reproduction assay (FSTRA). The molecular changes induced by APAP exposure were studied in liver and gonads by applying a previously developed combined FSTRA and proteomics approach. We observed a significant decrease in egg numbers, an increase in plasma hyaluronic acid, and the presence of single cell necrosis in liver tissue. Furthermore, nine common biomarkers (atp5f1b, etfa, uqcrc2a, cahz, c3a.1, rab11ba, mettl7a, khdrbs1a and si:dkey-108k21.24) for assessing hepatotoxicity were detected in both male and female liver, indicating hepatic damage. In comparison with exposure to fadrozole, an endocrine disrupting chemical (EDC), three potential biomarkers for liver injury, i.e. cahz, c3a.1 and atp5f1b, were differentially expressed. The zebrafish proteome response to fadrozole exposure indicated a significant regulation in estrogen synthesis and perturbed binding of sperm to zona pellucida in the ovary. This study demonstrates that biomarkers identified and quantified by proteomics can serve as additional weight-of-evidence for the discrimination of hepatotoxicity and endocrine disruption, which is necessary for hazard identification in EU legislation and to decide upon the option for risk assessment.


Assuntos
Biomarcadores/análise , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Disruptores Endócrinos/toxicidade , Monitoramento Ambiental/métodos , Proteômica/métodos , Acetaminofen/metabolismo , Acetaminofen/toxicidade , Animais , Biomarcadores/metabolismo , Diagnóstico Diferencial , Fadrozol/toxicidade , Feminino , Gônadas/efeitos dos fármacos , Masculino , Reprodução/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/metabolismo
2.
Talanta ; 205: 120108, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31450387

RESUMO

In this study, a capillary electrophoresis-tandem mass spectrometry method combining efficient separation and sensitive detection has been developed and validated, for the first time, to quantify acetaminophen and five of its metabolites in urine samples. Optimization of the method has led us to perform detection in positive ESI mode using MeOH-ammonium hydroxide (0.1%) (50:50, v/v) as sheath liquid. Moreover, optimal separation has been obtained in less than 9 min after anodic injection, using an ammonium acetate solution (40 mM, pH 10) as BGE. It was shown that the dilution solvent and the dilution factor to use for sample preparation are critical parameters to avoid peak splitting, to gain in sensitivity and then to obtain an effective analysis method. While a 200-fold factor dilution was shown to be suitable for quantitation of acetaminophen, acetaminophen mercapturate, acetaminophen sulfate and acetaminophen glucuronide, a 20-fold dilution was finally selected for methoxy-acetaminophen and 3-methylthioacetaminophen analysis, thus requiring two successive analyses to be carried out in order to quantify all metabolites. Hyphenation of CE with MS/MS versus UV permits to improve LOQ (10-20-fold factor with respect to previous works for acetaminophen, acetaminophen sulfate and acetaminophen glucuronide). Moreover, use of CE versus HPLC, permits to quantify two additional metabolites, i.e. 3-methylthio-acetaminophen and methoxy-acetaminophen. The method has been validated using the accuracy profile approach with a total error (accuracy) included in the ± 20% range. Thereby, the method allows the quantitation of acetaminophen and acetaminophen mercapturate in the range (0.1-1 mg mL-1), and of acetaminophen sulfate, methoxy-acetaminophen, acetaminophen glutathione and 3-methylthio-acetaminophen in the ranges (0.5-5 mg mL-1), (0.025-0.4 mg mL-1), (9.22-30 mg mL-1) and (0.073-0.4 mg mL-1), respectively. The method was finally applied to the analysis of urine samples of eighteen patients belonging to three different inclusion groups of the ongoing clinical trial, demonstrating that the method is suitable to highlight different metabolic profiles. This work will be subsequently extended to the analysis two hundred and seventy urine samples from patients included in a clinical trial dedicated to the study of acetaminophen metabolism changes after hepatic resection.


Assuntos
Acetaminofen/análogos & derivados , Acetaminofen/urina , Acetaminofen/metabolismo , Eletroforese Capilar/métodos , Humanos , Espectrometria de Massas em Tandem/métodos
3.
PLoS Comput Biol ; 15(6): e1007117, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31194730

RESUMO

Different pediatric physiologically-based pharmacokinetic (PBPK) models have been described incorporating developmental changes that influence plasma drug concentrations. Drug disposition into cerebrospinal fluid (CSF) is also subject to age-related variation and can be further influenced by brain diseases affecting blood-brain barrier integrity, like meningitis. Here, we developed a generic pediatric brain PBPK model to predict CSF concentrations of drugs that undergo passive transfer, including age-appropriate parameters. The model was validated for the analgesics paracetamol, ibuprofen, flurbiprofen and naproxen, and for a pediatric meningitis population by empirical optimization of the blood-brain barrier penetration of the antibiotic meropenem. Plasma and CSF drug concentrations derived from the literature were used to perform visual predictive checks and to calculate ratios between simulated and observed area under the concentration curves (AUCs) in order to evaluate model performance. Model-simulated concentrations were comparable to observed data over a broad age range (3 months-15 years postnatal age) for all drugs investigated. The ratios between observed and simulated AUCs (AUCo/AUCp) were within 2-fold difference both in plasma (range 0.92-1.09) and in CSF (range 0.64-1.23) indicating acceptable model performance. The model was also able to describe disease-mediated changes in neonates and young children (<3m postnatal age) related to meningitis and sepsis (range AUCo/AUCp plasma: 1.64-1.66, range AUCo/AUCp CSF: 1.43-1.73). Our model provides a new computational tool to predict CSF drug concentrations in children with and without meningitis and can be used as a template model for other compounds that passively enter the CNS.


Assuntos
Analgésicos , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Meningite/metabolismo , Modelos Biológicos , Acetaminofen/líquido cefalorraquidiano , Acetaminofen/metabolismo , Acetaminofen/farmacocinética , Adolescente , Adulto , Analgésicos/líquido cefalorraquidiano , Analgésicos/metabolismo , Analgésicos/farmacocinética , Química Encefálica/fisiologia , Criança , Pré-Escolar , Humanos , Lactente , Recém-Nascido
4.
Molecules ; 24(12)2019 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-31238523

RESUMO

Copper nanowires (Cu NWs) were modified with graphene oxide (GO) nanosheets to obtain a sensor for simultaneous voltammetric determination of ascorbic acid (AA), dopamine (DA) and acetaminophen (AC). The nanocomposite was obtained via sonication, and its structures were characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD) and energy-dispersive X-ray spectroscopy (EDS). The electrochemical oxidation activity of the materials (placed on a glassy carbon electrode) was studied by cyclic voltammetry and differential pulse voltammetry. Due to the synergistic effect of Cu NWs and GO, the specific surface, electrochemical oxidation performance and conductivity are improved when compared to each individual component. The peaks for AA (-0.08 V), DA (+0.16 V), and AC (+0.38 V) are well separated. The sensor has wide linear ranges which are from 1-60 µM, 1-100 µM, and 1-100 µM for AA, DA, and AC, respectively, when operated in the differential pulse voltammetric mode. The detection limits are 50, 410 and 40 nM, respectively. Potential interferences by uric acid (20 µM), glucose (10 mM), NaCl (1 mM), and KCl (1 mM) were tested for AA (1 µΜ), DA (1 µΜ), and AC (1 µΜ) and were found to be insignificant. The method was successfully applied to the quantification of AA, DA, and AC in spiked serum samples.


Assuntos
Cobre/química , Técnicas Eletroquímicas , Grafite/química , Nanoestruturas/química , Nanofios/química , Acetaminofen/sangue , Acetaminofen/metabolismo , Ácido Ascórbico/sangue , Ácido Ascórbico/metabolismo , Técnicas Biossensoriais , Dopamina/sangue , Dopamina/metabolismo , Humanos , Nanoestruturas/ultraestrutura , Nanofios/ultraestrutura , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
5.
Ecotoxicol Environ Saf ; 180: 610-615, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31132556

RESUMO

The frequent detection of paracetamol in natural water increased environmental concerns. The dielectric barrier discharge (DBD) technology is an effective paracetamol removing method, however, this research showed that the removal of paracetamol using DBD technology at 30 min dropped from 100% to 53.3% as the initial paracetamol concentration increased from 10 mg/L to 100 mg/L, due to the formation of more competitive intermediate products at higher paracetamol concentration. The removal of TOC was found to be much slower than that of paracetamol, as paracetamol was removed completely after 5 min treatment, the removal rate of TOC was 46.3% after 20 min treatment under 500 W discharge power and 50 mL/min air flow rate. The orthogonal experiment showed that the removal of TOC was significantly influenced by the treatment time, discharge power and recirculating flow rate, while less influenced by the discharge frequency. In the removal process of paracetamol, nitrite ion that generated during DBD treatment reacted with paracetamol to form an intermediate product of 3-nitro-4-acetamidophenol. The presence of nitrite ion retarded the removal of 3-nitro-4-acetamidophenol and thus the TOC, however, the nitrate ion did not. The degradation of paracetamol followed a sequence of 3-nitro-4-acetamidophenol, nitrosophenol/acetamide, N-methylacetamide, acetamide and small molecule organic acids in the DBD reactor, and these intermediates were finally oxidized to CO2, H2O and NO3-.


Assuntos
Acetaminofen/metabolismo , Nitritos/química , Poluentes Químicos da Água/metabolismo , Purificação da Água/métodos , Acetaminofen/química
6.
Environ Sci Pollut Res Int ; 26(13): 13539-13550, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30915694

RESUMO

In the current report, we examined the potential beneficial role of soursop fruit extract (SSFE) on liver injury induced by a single paracetamol (APAP) overdose (2000 mg/kg). Thirty-five Wistar albino rats were randomly divided into five groups as follows: control, SSFE, APAP, SSFE+APAP, and silymarin (SIL)+APAP. APAP intoxication was found to elevate alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and total bilirubin levels. Moreover, it increased the levels of malondialdehyde, nitrites, and nitrates and depleted glutathione, superoxide dismutase, catalase, glutathione reductase, and glutathione peroxidase. APAP intoxication inactivated the nuclear factor erythroid 2-related factor 2 (Nrf2) defense pathway and upregulated the expression of heme oxygenase-1 (HO-1). APAP administration enhanced the activation of nuclear factor-kappa B (NF-κB), the elevation of tumor necrosis factor-alpha and interleukin 1-beta levels, and the upregulation of inducible nitric oxide synthase mRNA expression. In addition, APAP activated the overexpression of Bax protein, increased release of cytochrome c, and the downregulation of Bcl-2 protein. Finally, APAP-induced overexpression of transforming growth factor-beta (TGF-ß) further suggested enhanced liver damage. On the other hand, SSFE pretreatment attenuated these biochemical, molecular, and histopathological alterations in the liver, which might be partially due to the regulation of hepatic Nrf2/HO-1 and downregulation of NF-κB and TGF-ß.


Assuntos
Acetaminofen/metabolismo , Anti-Inflamatórios/farmacologia , Antioxidantes/metabolismo , Aspartato Aminotransferases/metabolismo , Catalase/metabolismo , Frutas/metabolismo , Glutationa/metabolismo , Fígado/metabolismo , Malondialdeído/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Superóxido Dismutase/metabolismo , Acetaminofen/química , Alanina Transaminase/metabolismo , Animais , Annona , Anti-Inflamatórios/química , Antioxidantes/química , Apoptose , Aspartato Aminotransferases/química , Fator 2 Relacionado a NF-E2/química , Óxido Nítrico Sintase Tipo II/química , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/metabolismo , Verduras
7.
Pharmacol Rep ; 71(2): 257-265, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30822619

RESUMO

BACKGROUND: Non-opioid and opioid analgesics, as over-the-counter or prescribed medications, are widely used for the management of a diverse array of pathophysiological conditions. Previous studies have demonstrated the involvement of human cytosolic sulfotransferase (SULT) SULT1A1 in the sulfation of acetaminophen, O-desmethylnaproxen (O-DMN), and tapentadol. The current study was designed to investigate the impact of single nucleotide polymorphisms (SNPs) of the human SULT1A1 gene on the sulfation of these analgesic compounds by SULT1A1 allozymes. METHODS: Human SULT1A1 genotypes were identified by database search. cDNAs corresponding to nine SULT1A1 nonsynonymous missense coding SNPs (cSNPs) were generated by site-directed mutagenesis. Recombinant wild-type and SULT1A1 allozymes were bacterially expressed and affinity-purified. Purified SULT1A1 allozymes were analyzed for sulfation activity using an established assay procedure. RESULTS: Compared with the wild-type enzyme, SULT1A1 allozymes were shown to display differential sulfating activities toward three analgesic compounds, acetaminophen, O-desmethylnaproxen (O-DMN), and tapentadol, as well as the prototype substrate 4NP. CONCLUSION: Results obtained indicated clearly the impact of genetic polymorphisms on the drug-sulfation activity of SULT1A1 allozymes. Such information may contribute to a better understanding about the differential metabolism of acetaminophen, O-DMN, and tapentadol in individuals with different SULT1A1 genotypes.


Assuntos
Acetaminofen/metabolismo , Arilsulfotransferase/genética , Naproxeno/análogos & derivados , Tapentadol/metabolismo , Analgésicos não Entorpecentes/metabolismo , Analgésicos Opioides/metabolismo , Citosol/metabolismo , Escherichia coli/citologia , Genótipo , Humanos , Isoenzimas , Mutagênese Sítio-Dirigida , Naproxeno/metabolismo , Polimorfismo de Nucleotídeo Único , Sulfatos/metabolismo
8.
Chem Biol Interact ; 302: 123-134, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30794797

RESUMO

Paracetamol (N-acetyl-para amino phenol) is the most commonly used analgesic and antipyretic around the world. Its causes hepatotoxicity and nephrotoxicity at overdose or even at therapeutic doses. It is primarily metabolized by glucuronidation and sulfate conjugation. It is also metabolized by cytochrome-P450 system (CYP2E1, CYP1A2 and CYP 3A4), leading to the formation of N-acetyl-p-benzoquinoneimine (NAPQI). The present study was planned to investigate the influence of chrysin (known CYP2E1 and CYP3A4 inhibitor) on the bioactivation of paracetamol to NAPQI using rat liver microsomes in vitro and rats in vivo. Paracetamol (80 mg/kg) was administered orally without or with silymarin (100 mg/kg), a known CYP2E1 inhibitor and chrysin (100 and 200 mg/kg) to rats for 15 consecutive days. The area under the plasma concentration-time curve (AUC0-∞) and the peak plasma concentration (Cmax) of paracetamol were dose-dependently increased with chrysin (100 and 200 mg/kg) compared to paracetamol control group. On the other hand, the AUC0-∞ and Cmax of NAPQI were decreased significantly with chrysin (100 and 200 mg/kg). The elevated liver and kidney function markers were significantly reduced by chrysin and silymarin compared to paracetamol control group (P < 0.01). Histopathological studies of liver and kidney also well correlated with liver and kidney function tests. Chrysin also reduced the formation of NAPQI in the incubation samples of rat hepatocytes. The present study (both in vivo and in vitro) results revealed that chrysin might be inhibited the CYP2E1, CYP1A2 and CYP3A4-mediated metabolism of paracetamol; thereby decreased the formation of NAPQI and protected the liver and kidney.


Assuntos
Acetaminofen/metabolismo , Benzoquinonas/metabolismo , Flavonoides/farmacologia , Hepatócitos/efeitos dos fármacos , Iminas/metabolismo , Acetaminofen/sangue , Acetaminofen/farmacocinética , Administração Oral , Animais , Área Sob a Curva , Benzoquinonas/sangue , Benzoquinonas/farmacocinética , Cromatografia Líquida de Alta Pressão , Meia-Vida , Hepatócitos/citologia , Hepatócitos/metabolismo , Iminas/sangue , Iminas/farmacocinética , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Testes de Função Hepática , Masculino , Curva ROC , Ratos , Ratos Wistar , Silimarina/farmacologia
10.
Biochem Pharmacol ; 159: 25-31, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30423313

RESUMO

The activities of hundreds, perhaps thousands, of metabolites are regulated by human cytosolic sulfotransferases (SULTs) - a 13-member family of disease relevant enzymes that catalyze transfer of the sulfuryl moiety (-SO3) from PAPS (3'-phosphoadenosine 5'-phosphosulfonate) to the hydroxyls and amines of acceptors. SULTs harbor two independent allosteric sites, one of which, the focus of this work, binds non-steroidal anti-inflammatory drugs (NSAIDs). The structure of the first NSAID-binding site - that of SULT1A1 - was elucidated recently and homology modeling suggest that variants of the site are present in all SULT isoforms. The objective of the current study was to assess whether the NSAID-binding site can be used to regulate sulfuryl transfer in humans in an isoform specific manner. Mefenamic acid (Mef) is a potent (Ki 27 nM) NSAID-inhibitor of SULT1A1 - the predominant SULT isoform in small intestine and liver. Acetaminophen (APAP), a SULT1A1 specific substrate, is extensively sulfonated in humans. Dehydroepiandrosterone (DHEA) is specific for SULT2A1, which we show here is insensitive to Mef inhibition. APAP and DHEA sulfonates are readily quantified in urine and thus the effects of Mef on APAP and DHEA sulfonation could be studied non-invasively. Compounds were given orally in a single therapeutic dose to a healthy, adult male human with a typical APAP-metabolite profile. Mef profoundly decreased APAP sulfonation during first pass metabolism and substantially decreased systemic APAP sulfonation without influencing DHEA sulfonation; thus, it appears the NSAID site can be used to control sulfonation in humans in a SULT-isoform specific manner.


Assuntos
Acetaminofen/farmacocinética , Arilsulfotransferase/metabolismo , Ácido Mefenâmico/farmacocinética , Sulfotransferases/metabolismo , Acetaminofen/metabolismo , Acetaminofen/urina , Sítio Alostérico , Anti-Inflamatórios não Esteroides/metabolismo , Anti-Inflamatórios não Esteroides/farmacocinética , Arilsulfotransferase/antagonistas & inibidores , Arilsulfotransferase/química , Sítios de Ligação , Desidroepiandrosterona/administração & dosagem , Desidroepiandrosterona/metabolismo , Desidroepiandrosterona/urina , Interações de Medicamentos , Humanos , Isoenzimas/química , Isoenzimas/metabolismo , Espectroscopia de Ressonância Magnética , Ácido Mefenâmico/metabolismo , Ácido Mefenâmico/urina , Sulfotransferases/antagonistas & inibidores , Sulfotransferases/química
11.
Artigo em Inglês | MEDLINE | ID: mdl-30476594

RESUMO

Birds are exposed to many xenobiotics during their lifetime. For accurate prediction of xenobiotic-induced toxic effects on avian species, it is necessary to understand metabolic capacities in a comprehensive range of bird species. However, there is a lack of information about avian xenobiotic metabolizing enzymes (XMEs), particularly in wild birds. Uridine diphosphate glucuronosyltransferase (UGT) is an XME that plays an important role in phase II metabolism in the livers of mammals and birds. This study was performed to determine the characteristics of UGT1E isoform in avian species, those are related to mammals UGT 1A. To understand the characteristics of avian UGT1E isoforms, in vitro metabolic activity and genetic characteristics were investigated. Furthermore, mRNA expression levels of all chicken UGT1E isoforms were measured. On in vitro enzymatic analysis, the white-tailed eagle, great horned owl, and Humboldt penguin showed lower UGT-dependent activity than domestic birds. In synteny analysis, carnivorous birds were shown to have fewer UGT1E isoforms than herbivorous and omnivorous birds, which may explain why they have lower in vitro UGT activity. These observations suggested that raptors and seabirds, in which UGT activity is low, may be at high risk if exposed to elevated levels of xenobiotics in the environment. Phylogenetic analysis suggested that avian UGT1Es have evolved independently from mammalian UGT1As. We identified the important UGT isoforms, such as UGT1E13, and suspected their substrate specificities in avian xenobiotic metabolism by phylogenetic and quantitative real-time PCR analysis. This is the first report regarding the genetic characteristics and interspecies differences of UGT1Es in avian species.


Assuntos
Aves/genética , Regulação Enzimológica da Expressão Gênica/fisiologia , Glucuronosiltransferase/metabolismo , Acetaminofen/metabolismo , Analgésicos não Entorpecentes/metabolismo , Animais , Aves/metabolismo , Glucuronosiltransferase/genética , Microssomos Hepáticos/enzimologia , Filogenia , Especificidade da Espécie , Sintenia
12.
Environ Sci Pollut Res Int ; 26(1): 240-249, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30392171

RESUMO

Acetaminophen, APAP, is a common over-the-counter drug with antipyretic-analgesic action. When APAP is used in large doses, it causes hepatotoxicity and nephrotoxicity but safe at therapeutic doses. Cinnamon (Cinnamomum zeylanicum) is extensively used in folk medicine due to its high content of natural antioxidants. The current investigation was planned to study the possible ameliorative effect of cinnamon toward induced APAP-apoptosis and cellular damage in renal cells. Four groups (nine rats each) were used; negative control group administrated distilled water for 15 days; positive control APAP group administrated a single dose of APAP (1 g/kg) orally on the last day; APAP+Cin L (200 mg/kg) and APAP+Cin H (400 mg/kg) aqueous extract of cinnamon orally once a day for 15 days. An hour after the last dose of cinnamon, all rats in the third and fourth group were administrated a single dose of APAP (1 g/kg) orally. GC/MS analysis was performed to identify the plant used in the study. APAP markedly increased serum levels of creatinine, BUN, and glucose and decreased levels of albumin and total protein. In addition, APAP could also exert severe alteration in the kidney histopathology along with upregulation of caspase-3 and PCNA. However, pre-treatment with cinnamon ameliorated the APAP-induced cellular alterations and apoptosis, possibly through its high content of antioxidants.


Assuntos
Acetaminofen/toxicidade , Analgésicos não Entorpecentes/toxicidade , Cinnamomum zeylanicum/metabolismo , Acetaminofen/metabolismo , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Caspase 3 , Doença Hepática Induzida por Substâncias e Drogas/patologia , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Masculino , Óleos Voláteis/farmacologia , Ratos
13.
Artigo em Inglês | MEDLINE | ID: mdl-30268769

RESUMO

While it has been known for a while that some snake species are extremely sensitive to acetaminophen, the underlying mechanism for this toxicity has not been reported. To investigate if essential detoxification enzymes are missing in snake species that are responsible for biotransformation of acetaminophen in other vertebrate species, livers were collected from a variety of snake species, together with samples from alligator, snapping turtle, cat, rat, and cattle. Subcellular fractions were analyzed for enzymatic activities of phenol-type sulfotransferase and UDP­glucuronosyltransferase, total glutathione S­transferase, and N­acetyltransferase. The results showed that none of the snake species, together with the cat samples, had any phenol-type glucuronidation activity, and that this activity was much lower in alligator and turtle samples than in the mammalian species. Combined with the lack of N­acetyltransferase activity in snakes and cats, this would explain the accumulation of the aminophenol metabolite, which induces methemoglobinemia and subsequent suffocation of snakes and cats after acetaminophen exposure. While previous investigations have concluded that in cats the gene for the phenol-type glucuronosyltransferase isoform has turned into a pseudogene because of several point mutations, evaluation of genomic information for snake species revealed that they have only 2 genes that may code for glucuronosyltransferase isoforms. Similarity of these genes with mammalian genes is <50%, and suggests that the expressed enzymes may act on other types of substrates than aromatic amines. This indicates that the extreme sensitivity for acetaminophen in snakes is based on a different phylogenetic origin than the sensitivity observed in cats.


Assuntos
Acetaminofen/metabolismo , Poluentes Ambientais/metabolismo , Fígado/enzimologia , Filogenia , Proteínas de Répteis/metabolismo , Serpentes/fisiologia , Acetaminofen/efeitos adversos , Acetaminofen/toxicidade , Acetiltransferases/genética , Acetiltransferases/metabolismo , Agkistrodon/genética , Agkistrodon/fisiologia , Analgésicos não Entorpecentes/efeitos adversos , Analgésicos não Entorpecentes/metabolismo , Animais , Biotransformação , Boidae/genética , Boidae/fisiologia , Colubridae/genética , Colubridae/fisiologia , Crotalus/genética , Crotalus/fisiologia , Bases de Dados Genéticas , Resistência a Medicamentos , Poluentes Ambientais/toxicidade , Glucuronosiltransferase/genética , Glucuronosiltransferase/metabolismo , Glutationa Transferase/genética , Glutationa Transferase/metabolismo , Isoenzimas/genética , Isoenzimas/metabolismo , Proteínas de Répteis/genética , Serpentes/genética , Especificidade da Espécie , Sulfotransferases/genética , Sulfotransferases/metabolismo , Toxicocinética
14.
Pediatr Obes ; 14(1)2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30253079

RESUMO

BACKGROUND: High-throughput metabolomics has been used cross-sectionally to evaluate differential metabolic profiles associated with human obesity. OBJECTIVES: This study longitudinally assessed the cord blood metabolome to explore if metabolic signatures of obesity at age 3-5 are apparent at birth. METHODS: In a nested case-control design, metabolomics analysis was performed on umbilical cord blood of 25 children who developed obesity by age 3-5 years, compared with 25 sex-matched non-obese children enrolled as part of an ongoing birth cohort. Logistic regression models were used to identify significant metabolites, adjusting for maternal pre-pregnancy obesity. RESULTS: Children who had obesity by age 3-5 years had elevated levels of medium and long chain fatty acids including stearate, oleate and palmitate at birth. Children with obesity were also more likely to have elevated levels of acetaminophen metabolites at birth, specifically: 3-(N-acetyl-L-cystein-S-yl) acetaminophen, 2-hydroxyacetaminophen sulfate, 2-methoxyacetaminophen glucuronide and p-acetamidophenyl glucuronide. CONCLUSION: Although the observed increases in lipids are consistent with previous metabolomic studies of obesity, this study is the first to report associations between acetaminophen metabolites and obesity in children; however, we lack mechanistic insights for this link. Larger human studies with longer follow-up and laboratory-controlled animal experiments are needed to clarify associations.


Assuntos
Acetaminofen/metabolismo , Sangue Fetal/metabolismo , Metabolômica/métodos , Obesidade Pediátrica/sangue , Acetaminofen/sangue , Estudos de Casos e Controles , Pré-Escolar , Ácidos Graxos/sangue , Feminino , Humanos , Masculino , Gravidez
15.
Eur J Nutr ; 58(3): 955-964, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29322315

RESUMO

PURPOSE: Milk proteins and/or their hydrolysates have been reported to have beneficial effects for improving postprandial glycaemia. Gastric emptying is a major determinant of postprandial glycaemia, yet limited studies have examined the effects of intact milk proteins compared to hydrolysates on gastric emptying. We investigated gastric emptying of a casein hydrolysate compared to intact casein. METHODS: Nine overweight and obese adults (mean ± SD age: 59.5 ± 6.5 years and BMI 28.4 ± 2.6 kg/m2) were studied in a randomised crossover design. Gastric emptying was assessed by paracetamol absorption test, with HPLC-MS being used for determining paracetamol and its primary metabolites in plasma. Glucose, insulin and amino acid responses were also assessed. RESULTS: Linear mixed model analysis showed no effect of treatment [F(1, 55) = 2.1, P = 0.16] or treatment × time interactions [F(6, 54) = 1.5, P = 0.21] for paracetamol concentrations. In addition, there were no significant differences between the intact casein and hydrolysate for any of the gastric emptying outcome measures (Cmax, AUC0-30min, AUC0-60min; AUC0-240min). However, insulin was increased in the early postprandial period (iAUC0-15min, iAUC0-30min;P < 0.05) and there was a treatment effect for glucose [F(1, 53) = 5.3, P = 0.03] following the casein hydrolysate compared to intact casein. No significant differences in amino acids were found between the two conditions. CONCLUSIONS: Gastric emptying of a casein hydrolysate compared to intact casein does not differ. Mechanisms other than gastric emptying, for example the presence of a bioactive peptide sequence, may contribute to the glycaemic management effects of certain milk protein hydrolysates and warrant further investigation.


Assuntos
Aminoácidos/efeitos dos fármacos , Aminoácidos/metabolismo , Caseínas/farmacologia , Esvaziamento Gástrico/efeitos dos fármacos , Acetaminofen/metabolismo , Adulto , Idoso , Estudos Cross-Over , Feminino , Glucose/metabolismo , Humanos , Insulina/sangue , Masculino , Pessoa de Meia-Idade , Período Pós-Prandial
16.
Surg Today ; 49(1): 38-48, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30159780

RESUMO

PURPOSE: Functional outcomes were prospectively compared between two types of reconstruction [double tract (L-DT; n = 15) and jejunal interposition (L-JIP; n = 15)] following laparoscopic half-proximal gastrectomy (LPG), including laparoscopic total gastrectomy (L-TG; n = 30) as a control group, at 1 year after surgery. METHODS: Clinical investigations were performed in each patient, and functional evaluations, involving the swallowing of an alimentary liquid containing acetaminophen (AAP), followed by measurements of the concentrations of AAP and hormones in the sitting (n = 5) and in the supine positions (n = 5), were carried out in each group. RESULTS: The post-/preoperative body weight ratios were significantly higher in the L-DT and L-JIP groups than in the L-TG group. The AAP levels were significantly lower in the LPG group than in the LTG group. The AAP, insulin, and gastrin levels in the L-JIP group were markedly increased in the sitting position compared with the supine position, while those in the L-DT and L-TG groups were stable in both positions. CONCLUSIONS: L-JIP and L-DT are procedures that maintain gradual intestinal absorption and help improve the quality of life. Intestinal absorption and hormonal secretion were relatively unaffected by the posture of the meal intake after L-DT, so L-DT might be the procedure providing the most stable results.


Assuntos
Gastrectomia/métodos , Jejuno/cirurgia , Laparoscopia/métodos , Procedimentos Cirúrgicos Reconstrutivos/métodos , Neoplasias Gástricas/cirurgia , Estômago/cirurgia , Acetaminofen/metabolismo , Idoso , Peso Corporal , Feminino , Gastrinas/metabolismo , Humanos , Insulina/metabolismo , Absorção Intestinal , Masculino , Pessoa de Meia-Idade , Período Perioperatório , Postura/fisiologia , Estudos Prospectivos , Qualidade de Vida , Neoplasias Gástricas/metabolismo , Fatores de Tempo
17.
Sci Total Environ ; 649: 431-439, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30176456

RESUMO

Many pharmaceutical and personal care products (PPCPs) enter agroecosystems during reuse of treated wastewater and biosolids, presenting potential impacts on plant development. Here, acetaminophen, one of the most-used pharmaceuticals, was used to explore roles of glutathione (GSH) conjugation in its biotransformation in crop plants. Acetaminophen was taken up by plants, and conjugated quickly with GSH. After exposure to 5 mg L-1 acetaminophen for 144 h, GSH-acetaminophen conjugates were 15.2 ±â€¯1.3 nmol g-1 and 1.2 ±â€¯0.1 nmol g-1 in cucumber roots and leaves, respectively. Glutathione-acetaminophen was also observed in common bean, alfalfa, tomato, and wheat. Inhibition of cytochrome P450 decreased GSH conjugation. Moreover, the GSH conjugate was found to further convert to cysteine and N-acetylcysteine conjugates. Glutathione S-transferase activity was significantly elevated after exposure to acetaminophen, while levels of GSH decreased by 55.4% in roots after 48 h, followed by a gradual recovery thereafter. Enzymes involved in GSH synthesis, regeneration and transport were consistently induced to maintain the GSH homeostasis. Therefore, GST-mediated conjugation likely played a crucial role in minimizing phytotoxicity of acetaminophen and other PPCPs in plants.


Assuntos
Acetaminofen/metabolismo , Cucumis sativus/metabolismo , Glutationa Transferase/metabolismo , Proteínas de Plantas/metabolismo , Poluentes do Solo/metabolismo , Poluentes Químicos da Água/metabolismo , Analgésicos não Entorpecentes/metabolismo , Antipiréticos/metabolismo , Biodegradação Ambiental , Cucumis sativus/enzimologia , Inativação Metabólica
18.
Chem Commun (Camb) ; 54(83): 11745-11748, 2018 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-30276401

RESUMO

Tumor biomarkers are highly desirable for the screening of patients with a risk of tumor development and progression. Here, we report a beta-galactosidase (ß-gal)-responsive acetaminophen (ß-GR-APAP) as a synthetic plasma biomarker for targeted tumor detection. Tumor ß-gal labeling via the recognition of tumor-related antigen enabled the detection of a tumor using ß-GR-APAP.


Assuntos
Acetaminofen/análogos & derivados , Antígenos de Neoplasias/análise , Neoplasias/diagnóstico , beta-Galactosidase/metabolismo , Acetaminofen/metabolismo , Animais , Antígenos de Neoplasias/metabolismo , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Humanos , Camundongos , Neoplasias/metabolismo , Coloração e Rotulagem/métodos
19.
Drug Des Devel Ther ; 12: 3071-3084, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30275684

RESUMO

Purpose: This study is aimed at preparing and testing physicochemical, pharmacokinetic and levels of toxic metabolites of paracetamol and glucosamine solid dispersions intended for multiple deliveries via the parenteral or per oral route. Methods: Solid dispersions were prepared using the spray drying technique at different molar ratios of paracetamol and glucosamine. Characterization of the solid dispersions was carried out using differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), scanning electron microscopy (SEM), equilibrium solubility and intrinsic dissolution rate. In vivo pharmacokinetics and toxic metabolites of the prepared dispersions were evaluated and compared to those of pure drugs and physical mixtures. Results: Instant water solubility and more than 7-fold increase in dissolution rate led to significantly high plasma drug concentration (>6.5-fold) compared to paracetamol alone. More than 2-fold increase in area under the curve from 0 to 24 h from the dispersions was noticed on the third day of oral dosing to animals. Lower number and concentration followed by the complete disappearance of toxic pathway metabolites were observed on second and third days of dosing with solid dispersions and physical mixtures, respectively. Conclusions: The spray-dried dispersions support safer and more effective delivery of multiple doses of paracetamol, leading to an acceleration of its analgesic actions. Synergism between the analgesic actions of paracetamol and joint protective actions of glucosamine in this combination is expected to facilitate effective treatment of persistent pain-related illnesses such as osteoarthritis.


Assuntos
Acetaminofen/farmacocinética , Glucosamina/farmacocinética , Acetaminofen/metabolismo , Acetaminofen/toxicidade , Administração Oral , Animais , Disponibilidade Biológica , Química Farmacêutica , Glucosamina/metabolismo , Glucosamina/toxicidade , Fígado/metabolismo , Masculino , Conformação Molecular , Tamanho da Partícula , Coelhos , Solubilidade , Propriedades de Superfície
20.
Anal Chim Acta ; 1041: 33-39, 2018 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-30340688

RESUMO

Robotic square wave voltammetry (SVW) in 24-well microtiter plates has been developed as a reliable non-manual procedure for quantifying drug release from pharmaceutical hydrogels. The assay was established using 1% agarose disks containing Paracetamol® (PCT) as a model preparation. Computerized buffer delivery and SVW in calibration and hydrogel sample wells were performed by a three-electrode arrangement combined with a thin plastic tube. For the glassy carbon working electrode of the assembly the upper limit of the linear response and the lower detection limit of sequential 'in-well' PCT-SVW were 1000 and 0.5 µM, respectively. During non-stop runs through plate wells with equal drug titers the voltammetric PCT signal was stable for at least 6 h. For the construction of drug-release curves with triplicate data points PCT-SVW was performed sequentially on three identical hydrogel samples in neighboring plate wells, preceded and followed by sensor calibrations for response validation. The results showed bi-phasic PCT release profiles exhibiting an initial rapid loss of the drug near the surface of the gel, followed by slowly decelerating release of more deeply buried drug and the dissipation of the concentration gradient that drives diffusion. The proposed automation of voltammetric testing generates reliable hydrogel drug release profiles without the need for operator intervention, avoiding human errors from monotonous manual electroanalysis and releasing skilled staff for other work. This approach is therefore suggested as an economic option for hydrogel dissolution testing in academic or industrial R&D, particularly when the required multi-parameter optimization creates many samples.


Assuntos
Acetaminofen/análise , Técnicas Eletroquímicas/métodos , Hidrogéis/química , Robótica , Acetaminofen/metabolismo , Automação , Liberação Controlada de Fármacos , Eletrodos , Humanos , Limite de Detecção , Análise em Microsséries
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