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1.
Environ Sci Pollut Res Int ; 28(2): 1762-1774, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32856245

RESUMO

The current study aimed to investigate the protective effect of corn silk methanolic extract (CSME) against acetaminophen (APAP)-induced nephrotoxicity. The present study was carried out on 40 male Wistar albino rats, which were randomly divided into four groups (n = 10): control group, orally administered with a single dose of 1.8 ml 0.9% normal saline at the last day of the experiment; CSME group, orally received CSME (400 mg/kg BW daily for 5 weeks); APAP group, orally administered with a single dose of APAP (2 g/kg BW); and CSME and APAP group, orally administered with CSME, followed by a single oral dose of APAP. The results of this study revealed that APAP caused a significant increase in serum urea, creatinine concentrations, and malondialdehyde (MDA) concentrations in renal tissues. In addition, APAP caused a significant decrease in superoxide dismutase (SOD) and glutathione peroxidase (GPX) activities in renal tissues compared with the control group. Furthermore, APAP caused marked renal damage as revealed by alterations in histopathological architectures of kidney tissues. APAP resulted in a marked expression of caspase 3 and nuclear factor κB (NFĸß) within the renal tubules, while caused marked decrease of proliferating cell nuclear antigen (PCNA) immunostaining and transforming growth factor beta 1 (TGFß 1) expression within the epithelial lining of the renal tubules. However, pre-treatment with CSME returned all biochemical parameters, histopathological changes, and immunohistochemical parameters toward normal levels as the control group. In conclusion, oral administration of CSME protected rats against APAP renal toxicity through its antioxidant, anti-apoptotic, and anti-inflammatory protective mechanisms.


Assuntos
Acetaminofen , Doença Hepática Induzida por Substâncias e Drogas , Acetaminofen/metabolismo , Acetaminofen/toxicidade , Animais , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Rim/metabolismo , Fígado/metabolismo , Masculino , Estresse Oxidativo , Extratos Vegetais/metabolismo , Extratos Vegetais/farmacologia , Ratos , Ratos Wistar , Seda/metabolismo , Zea mays
2.
Environ Toxicol ; 35(11): 1251-1259, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32677766

RESUMO

Isatidis Folium (IF) has been clinically combined with acetaminophen (APAP), but the rationality of combinational therapy is still ambiguous. In the present study, the protective effect and related mechanism of IF on APAP-induced hepatotoxicity were evaluated. Hepatic histopathology and blood biochemistry investigations clearly demonstrated that IF could restore APAP-induced hepatotoxicity. Liver distribution study indicated that the hepatoprotective effect of IF on APAP is attributed to the reduction of N-acetyl-p-benzoquinone imine (NAPQI) in liver, which is a known hepatotoxic metabolite of APAP. Further study suggested the reduction is not via decreasing the generation of NAPQI through inhibiting the enzyme activities of CYP 1A2, 2E1, and 3A4 but via accelerating the transformation of NAPQI to NAPQI-GSH by promoting GSH and decreasing GSSG contents in liver. Furthermore, IF significantly enhanced the hepatic activities of GSH-associated enzymes in APAP-treated mice. In summary, IF could alleviate APAP-induced hepatotoxicity by reducing the content of NAPQI via enhancing the level of GSH and the followed generation of NAPQI-GSH which might be ascribed to the upregulation of GSH-associated enzymes.


Assuntos
Acetaminofen/toxicidade , Antioxidantes/metabolismo , Extratos Vegetais/farmacologia , Acetaminofen/metabolismo , Animais , Benzoquinonas , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Crônica Induzida por Substâncias e Drogas/patologia , Citocromo P-450 CYP1A2 , Glutationa/metabolismo , Iminas , Fígado/efeitos dos fármacos , Masculino , Camundongos , Folhas de Planta
3.
Chemosphere ; 260: 127532, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32683017

RESUMO

Acetaminophen (APAP), a widely used analgesic-antipyretic drug, is frequently detected in the environment and may pose ecological risks to aquatic communities. In this work, an APAP-degrading organism, designated as Ensifer sp. POKHU, was isolated from activated sludge (AS) enriched with APAP. POKHU degraded up to 630 mg/L of APAP without substrate inhibition. The bacterium metabolized APAP to hydroquinone (HQ) via 4-aminophenol (4-AP). APAP derivatives, 4AP, HQ, and 1,4-benzoquinone (BQ), frequently detected in the environment, were found to inhibit nitrogen metabolism (ammonium oxidation) to a greater extent than APAP. POKHU had the ability to degrade varying levels (0.4-40 mg/L) of 4-AP, HQ, and BQ, which indicated a great potential for detoxification in environments contaminated with both APAP and its derivatives. The addition of POKHU to fresh AS samples taken from a wastewater treatment plant greatly increased the biotransformation rates of APAP from 5.6 d-1 (no POKHU augmentation) to >20.0 d-1 (5% POKHU). Bioaugmentation with POKHU reduced 400 µg/L of APAP to levels below its ecotoxicity threshold within 4 h, which is shorter than the typical hydraulic retention times for full-scale AS processing. Overall, this study identified a new auxiliary biological agent for APAP detoxification, which could degrade both APAP and its metabolic derivatives (those that can be more toxic than the parent contaminant, APAP). The results have practical implications for developing a biological means (detoxification and bioaugmentation) of treating high-strength pharmaceutical waste streams, such as wastewater from hospitals and drug manufactures, and of landfill leachates.


Assuntos
Acetaminofen/metabolismo , Biodegradação Ambiental , Rhizobiaceae/isolamento & purificação , Esgotos/microbiologia , Purificação da Água/métodos , Acetaminofen/análogos & derivados , Acetaminofen/química , Analgésicos não Entorpecentes/metabolismo , Biotransformação , Hidroquinonas/metabolismo , Cinética , Rhizobiaceae/metabolismo , Águas Residuárias/química , Poluentes Químicos da Água/química
4.
Microb Cell Fact ; 19(1): 105, 2020 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-32430011

RESUMO

BACKGROUND: 2-Acetamidophenol (AAP) is an aromatic compound with the potential for antifungal, anti-inflammatory, antitumor, anti-platelet, and anti-arthritic activities. Due to the biosynthesis of AAP is not yet fully understood, AAP is mainly produced by chemical synthesis. Currently, metabolic engineering of natural microbial pathway to produce valuable aromatic compound has remarkable advantages and exhibits attractive potential. Thus, it is of paramount importance to develop a dominant strain to produce AAP by elucidating the AAP biosynthesis pathway. RESULT: In this study, the active aromatic compound AAP was first purified and identified in gene phzB disruption strain HT66ΔphzB, which was derived from Pseudomonas chlororaphis HT66. The titer of AAP in the strain HT66ΔphzB was 236.89 mg/L. Then, the genes involved in AAP biosynthesis were determined. Through the deletion of genes phzF, Nat and trpE, AAP was confirmed to have the same biosynthesis route as phenazine-1-carboxylic (PCA). Moreover, a new arylamine N-acetyltransferases (NATs) was identified and proved to be the key enzyme required for generating AAP by in vitro assay. P. chlororaphis P3, a chemical mutagenesis mutant strain of HT66, has been demonstrated to have a robust ability to produce antimicrobial phenazines. Therefore, genetic engineering, precursor addition, and culture optimization strategies were used to enhance AAP production in P. chlororaphis P3. The inactivation of phzB in P3 increased AAP production by 92.4%. Disrupting the phenazine negative regulatory genes lon and rsmE and blocking the competitive pathway gene pykA in P3 increased AAP production 2.08-fold, which also confirmed that AAP has the same biosynthesis route as PCA. Furthermore, adding 2-amidophenol to the KB medium increased AAP production by 64.6%, which suggested that 2-amidophenol is the precursor of AAP. Finally, by adding 5 mM 2-amidophenol and 2 mM Fe3+ to the KB medium, the production of AAP reached 1209.58 mg/L in the engineered strain P3ΔphzBΔlonΔpykAΔrsmE using a shaking-flask culture. This is the highest microbial-based AAP production achieved to date. CONCLUSION: In conclusion, this study clarified the biosynthesis process of AAP in Pseudomonas and provided a promising host for industrial-scale biosynthesis of AAP from renewable resources.


Assuntos
Acetaminofen/metabolismo , Arilamina N-Acetiltransferase/metabolismo , Vias Biossintéticas , Engenharia Metabólica , Pseudomonas chlororaphis/enzimologia , Arilamina N-Acetiltransferase/genética , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Genes Bacterianos , Microbiologia Industrial , Pseudomonas chlororaphis/genética
5.
Drug Metab Pharmacokinet ; 35(3): 329-333, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32307228

RESUMO

Physiological and drug-specific parameters need to be adjusted when extrapolating a pharmacokinetic (PK) model from adults to neonates, so as to reproduce the time profiles of the studied drug(s) consistent with clinical, in vivo data or in vitro cell line measurements. In this paper we present a parameter analysis method, i.e. the Latin Hypercube Sampling (LHS) method for an acetaminophen (APAP) PK model. The original model consists of two compartments (the blood and the urine) with Michaelis-Menten kinetic parameters determined for APAP and its metabolites. The physiological parameters are scaled through allometric laws from adults to neonates, and APAP-specific parameters are adjusted for enzymatic maturational changes. The LHS method is used to statistically investigate the interplay between these parameters. The results for the extrapolated APAP model are consistent with published APAP PK data in neonates. We found the sulphation clearance parameter played a crucial role in the neonatal PK model, but its influence was weakened if the volume of distribution parameters were included. We suggest that this kind of in silico experiment could be valuable as the first step in PK model extrapolation between different ages.


Assuntos
Acetaminofen/farmacocinética , Envelhecimento/metabolismo , Modelos Biológicos , Acetaminofen/análise , Acetaminofen/metabolismo , Adulto , Fatores Etários , Relação Dose-Resposta a Droga , Humanos , Recém-Nascido , Cinética
6.
Bioanalysis ; 12(7): 485-500, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32343149

RESUMO

A U(H)PLC-MS/MS method is described for the analysis of acetaminophen and its sulphate, glucuronide, glutathione, cysteinyl and N-acetylcysteinyl metabolites in plasma using stable isotope-labeled internal standards. P-Aminophenol glucuronide and 3-methoxyacetaminophen were monitored and semi-quantified using external standards. The assay takes 7.5 min/sample, requires only 5 µl of plasma and involves minimal sample preparation. The method was validated for rat plasma and cross validated for human and pig plasma and mouse serum. LOQ in plasma for these analytes were 0.44 µg/ml (APAP-C), 0.58 µg/ml (APAP-SG), 0.84 µg/ml (APAP-NAC), 2.75 µg/ml (APAP-S), 3.00 µg/ml (APAP-G) and 16 µg/ml (APAP). Application of the method is illustrated by the analysis of plasma following oral administration of APAP to male Han Wistar rats.


Assuntos
Acetaminofen/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Plasma/metabolismo , Espectrometria de Massas em Tandem/métodos , Animais , Humanos , Ratos , Ratos Wistar , Suínos
7.
Chem Biol Interact ; 322: 109056, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32198084

RESUMO

Cytochrome P450 (P450) 2E1 is the major P450 enzyme involved in ethanol metabolism. That role is shared with two other enzymes that oxidize ethanol, alcohol dehydrogenase and catalase. P450 2E1 is also involved in the bioactivation of a number of low molecular weight cancer suspects, as validated in vivo in mouse models where cancers could be attenuated by deletion of Cyp2e1. P450 2E1 does not have a role in global production of reactive oxygen species but localized roles are possible, e.g. in mitochondria. The structures, conformations, and catalytic mechanisms of P450 2E1 have some unusual features among P450s. The concentration of hepatic P450 varies ≥10-fold among humans, possibly in part due to single nucleotide variants. The level of P450 2E1 may have relevance in the rates of oxidation of drugs, particularly acetaminophen and anesthetics.


Assuntos
Citocromo P-450 CYP2E1/metabolismo , Neoplasias/patologia , Acetaminofen/química , Acetaminofen/metabolismo , Animais , Carcinógenos/química , Carcinógenos/metabolismo , Citocromo P-450 CYP2E1/deficiência , Citocromo P-450 CYP2E1/genética , Etanol/química , Etanol/metabolismo , Humanos , Cinética , Mitocôndrias/metabolismo , Neoplasias/metabolismo , Espécies Reativas de Oxigênio/metabolismo
8.
Arterioscler Thromb Vasc Biol ; 40(5): 1207-1219, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32188278

RESUMO

OBJECTIVE: Intravenous acetaminophen/paracetamol (APAP) is well documented to cause hypotension. Since the patients receiving intravenous APAP are usually critically ill, any severe hemodynamic changes, as with those associated with APAP, can be life-threatening. The mechanism underlying this dangerous iatrogenic effect of APAP was unknown. Approach and Results: Here, we show that intravenous APAP caused transient hypotension in rats, which was attenuated by the Kv7 channel blocker, linopirdine. APAP metabolite N-acetyl-p-benzoquinone imine caused vasodilatation of rat mesenteric arteries ex vivo. This vasodilatation was sensitive to linopirdine and also the calcitonin gene-related peptide antagonist, BIBN 4096. Further investigation revealed N-acetyl-p-benzoquinone imine stimulates calcitonin gene-related peptide release from perivascular nerves, causing a cAMP-dependent activation of Kv7 channels. We also show that N-acetyl-p-benzoquinone imine enhances Kv7.4 and Kv7.5 channels overexpressed in oocytes, suggesting that it can activate Kv7.4 and Kv7.5 channels directly, to elicit vasodilatation. CONCLUSIONS: Direct and indirect activation of Kv7 channels by the APAP metabolite N-acetyl-p-benzoquinone imine decreases arterial tone, which can lead to a drop in blood pressure. Our findings provide a molecular mechanism and potential preventive intervention for the clinical phenomenon of intravenous APAP-dependent transient hypotension.


Assuntos
Acetaminofen/toxicidade , Pressão Sanguínea/efeitos dos fármacos , Hipotensão/induzido quimicamente , Canais de Potássio KCNQ/agonistas , Artérias Mesentéricas/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Acetaminofen/metabolismo , Animais , Benzoquinonas , Hipotensão/metabolismo , Hipotensão/fisiopatologia , Iminas , Canais de Potássio KCNQ/genética , Canais de Potássio KCNQ/metabolismo , Masculino , Potenciais da Membrana , Artérias Mesentéricas/metabolismo , Artérias Mesentéricas/fisiopatologia , Ratos Wistar , Transdução de Sinais , Xenopus laevis
9.
Biol Pharm Bull ; 43(2): 195-206, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32009106

RESUMO

Acetaminophen (paracetamol, N-acetyl-p-aminophenol; APAP) is the most popular analgesic/antipyretic agent in the world. APAP has been regarded as a safer drug compared with non-steroidal anti-inflammatory drugs (NSAIDs) particularly in terms of lower risks of renal dysfunction, gastrointestinal injury, and asthma/bronchospasm induction, even in high-risk patients such as the elderly, children, and pregnant women. On the other hand, the recent increasing use of APAP has raised concerns about its toxicity. In this article, we review recent pharmacological and toxicological findings about APAP from basic, clinical, and epidemiological studies, including spontaneous drug adverse events reporting system, especially focusing on drug-induced asthma and pre-and post-natal closure of ductus arteriosus. Hepatotoxicity is the greatest fault of APAP and the most frequent cause of drug-induced acute liver failure in Western countries. However, its precise mechanism remains unclear and no effective cure beyond N-acetylcysteine has been developed. Recent animal and cellular studies have demonstrated that some cellular events, such as c-jun N-terminal kinase (JNK) pathway activation, endoplasmic reticulum (ER) stress, and mitochondrial oxidative stress may play important roles in the development of hepatitis. Herein, the molecular mechanisms of APAP hepatotoxicity are summarized. We also discuss the not-so-familiar "dark side" of APAP as an otherwise safe analgesic/antipyretic drug.


Assuntos
Acetaminofen/efeitos adversos , Acetaminofen/metabolismo , Analgésicos não Entorpecentes/efeitos adversos , Analgésicos não Entorpecentes/metabolismo , Antipiréticos/efeitos adversos , Antipiréticos/metabolismo , Acetilcisteína , Idoso , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Feminino , Glutationa , Humanos , Masculino , Mitocôndrias Hepáticas/efeitos dos fármacos , Estresse Oxidativo , Gravidez
10.
Mol Pharmacol ; 97(4): 278-286, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32029527

RESUMO

Acetaminophen (APAP) is a commonly used over-the-counter drug for its analgesic and antipyretic effects. However, APAP overdose leads to severe APAP-induced liver injury (AILI) and even death as a result of the accumulation of N-acetyl-p-benzoquinone imine, the toxic metabolite of APAP generated by cytochrome P450s (P450s). Long noncoding RNAs HNF1α antisense RNA 1 (HNF1α-AS1) and HNF4α antisense RNA 1 (HNF4α-AS1) are regulatory RNAs involved in the regulation of P450 expression in both mRNA and protein levels. This study aims to determine the impact of HNF1α-AS1 and HNF4α-AS1 on AILI. Small hairpin RNAs were used to knock down HNF1α-AS1 and HNF4α-AS1 in HepaRG cells. Knockdown of these lncRNAs altered APAP-induced cytotoxicity, indicated by MTT and LDH assays. Specifically, HNF1α-AS1 knockdown decreased APAP toxicity with increased cell viability and decreased LDH release, whereas HNF4α-AS1 knockdown exacerbated APAP toxicity, with opposite effects in the MTT and LDH assays. Alterations on gene expression by knockdown of HNF1α-AS1 and HNF4α-AS1 were examined in several APAP metabolic pathways, including CYP1A2, CYP2E1, CYP3A4, UGT1A1, UGT1A9, SULT1A1, GSTP1, and GSTT1. Knockdown of HNF1α-AS1 decreased mRNA expression of CYP1A2, 2E1, and 3A4 by 0.71-fold, 0.35-fold, and 0.31-fold, respectively, whereas knockdown of HNF4α-AS1 induced mRNAs of CYP1A2, 2E1, and 3A4 by 1.3-fold, 1.95-fold, and 1.9-fold, respectively. These changes were also observed in protein levels. Knockdown of HNF1α-AS1 and HNF4α-AS1 had limited effects on the mRNA expression of UGT1A1, UGT1A9, SULT1A1, GSTP1, and GSTT1. Altogether, our study suggests that HNF1α-AS1 and HNF4α-AS1 affected AILI mainly through alterations of P450-mediated APAP biotransformation in HepaRG cells, indicating an important role of the lncRNAs in AILI. SIGNIFICANCE STATEMENT: The current research identified two lncRNAs, hepatocyte nuclear factor 1α antisense RNA 1 and hepatocyte nuclear factor 4α antisense RNA 1, which were able to affect susceptibility of acetaminophen (APAP)-induced liver injury in HepaRG cells, possibly through regulating the expression of APAP-metabolizing cytochrome P450 enzymes. This discovery added new factors, lncRNAs, which can be used to predict cytochrome P450-mediated drug metabolism and drug-induced toxicity.


Assuntos
Acetaminofen/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/genética , Sistema Enzimático do Citocromo P-450/genética , Hepatócitos/efeitos dos fármacos , RNA Longo não Codificante/metabolismo , Acetaminofen/metabolismo , Linhagem Celular , Doença Hepática Induzida por Substâncias e Drogas/patologia , Sistema Enzimático do Citocromo P-450/metabolismo , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Predisposição Genética para Doença , Hepatócitos/patologia , Humanos , Fígado/citologia , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/patologia , RNA Longo não Codificante/genética , RNA Interferente Pequeno/metabolismo
11.
Xenobiotica ; 50(6): 654-662, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31631733

RESUMO

1. The expression and activity of drug-metabolizing enzymes are known to affect the pharmacokinetics of drugs metabolized in the liver. Here, we assessed the effect of acetaminophen (APAP)-induced hepatotoxicity on the mRNA expression of drug-metabolizing enzymes and elucidated the underlying mechanism using three-dimensional (3D) cultures of HepG2 cells.2. 3D culture cells enabled us to establish an in vitro model of APAP-induced hepatotoxicity which showed the increase in N-acetyl-p-benzoquinone imine production, reactive oxygen species (ROS) generation and cellular injury.3. In this 3D culture model, APAP treatment significantly increased the mRNA expression of drug-metabolizing enzymes (cytochrome P450 [CYP]3A4, CYP2E1 and UDP-glucuronosyltransferase 1A6) and their nuclear receptors (pregnane X receptor and constitutive androstane receptor) compared with untreated cells. Treatment with N-acetylcysteine, a therapeutic agent for APAP-induced hepatotoxicity, suppressed these increases. In addition, the mRNA expression of drug-metabolizing enzymes and nuclear receptors were elevated depending on the concentration of H2O2, one of ROS involved in the development of APAP-induced hepatotoxicity. The mRNA expression of nuclear receptors increased before that of drug-metabolizing enzymes.4. In conclusion, ROS may induce the mRNA expression of nuclear receptors and promote the transcription of drug-metabolizing enzymes in the in vitro model of APAP-induced hepatotoxicity.


Assuntos
Acetaminofen/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , RNA Mensageiro/metabolismo , Acetaminofen/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/genética , Citocromo P-450 CYP2E1/metabolismo , Células Hep G2 , Hepatócitos/metabolismo , Humanos , Inativação Metabólica , Fígado , Taxa de Depuração Metabólica , Receptores Citoplasmáticos e Nucleares
12.
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
13.
Clin Toxicol (Phila) ; 58(1): 62-64, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31050299

RESUMO

Introduction: Several reports describe high anion gap metabolic acidosis with 5-oxoproline (5-OP) after acetaminophen exposure, including therapeutic use of acetaminophen. The mechanism may involve disordered glutathione metabolism. It is unknown whether acute acetaminophen overdose consistently causes elevations in 5-oxoproline concentration.Methods: We enrolled 23 consecutive adult and adolescent patients with measureable plasma APAP after acute APAP overdose. We used plasma left over in the laboratory after blood tests obtained in clinical care of the patients. We measured plasma [5-OP] by GC/MS. We compared the [5-OP] to laboratory results obtained in the care of these patients to search for correlations. The study had IRB approval.Results: Eighteen patients had non-detectable or normal (<100 µmol/L) 5-oxoproline concentrations. Six more patients had concentrations between 100 µmol/L and 300 µmol/L. There was no significant correlation of 5-OP with APAP, AST, ALT, creatinine, anion gap, INR, or total bilirubin.Discussion: Limitations of the study include small sample size and treatment with IV N-acetylcysteine for all patients with APAP concentrations above the 150 line of the Rumack Matthew nomogram or with hepatotoxicity. We believe that inherited enzyme deficiencies more likely explain cases of 5-oxoprolinemia.Conclusion: Acetaminophen overdose generally results in normal 5-oxoproline concentrations with some patients having slightly elevated 5-oxoproline concentrations.


Assuntos
Acetaminofen/envenenamento , Overdose de Drogas/sangue , Ácido Pirrolidonocarboxílico/sangue , Acetaminofen/sangue , Acetaminofen/metabolismo , Adolescente , Adulto , Idoso , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Pessoa de Meia-Idade , Adulto Jovem
14.
Sci Total Environ ; 703: 134990, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-31740064

RESUMO

Acetaminophen (APAP), which is an active ingredient of many analgesic drugs, is one of the contaminants of emerging concern in the environment. Although APAP is biodegradable, it is frequently detected in treatment plant effluents, surface water and soil suggesting that there are factors affecting the fate of APAP in the environment. In this study, four strains of bacteria that can degrade APAP were isolated from soil. Those strains belonged to Rhodococcus, Pseudomonas, Flavobacterium, and Sphingobium genera of Bacteria. A series of kinetic experiments were performed on the isolates in shake-flasks to determine biodegradation rate constant as well as the effect of temperature, APAP concentration and cell density on the biodegradation rates. APAP biodegradation follows the first order reaction kinetics which is coupled with cell growth. The specific APAP biodegradation rate constant (k) for all strains was similar and equal to 0.19 ±â€¯0.01 h-1. The temperature, at which APAP biodegradation rate was maximum, was 35 °C. APAP biodegradation rate was linearly correlated with both the initial APAP concentration and the cell density. Initial step of the APAP biodegradation was hydrolysis of the amide bond which resulted in formation and accumulation of p-aminophenol suggesting that aryl acylamidase enzyme is responsible for the biotransformation. In addition, free and immobilized crude enzymes of the isolates transformed APAP at similar rates, comparable to the intact cells. This study showed that APAP biodegradation is achieved by a diverse group of bacteria having a similar enzyme operating at a constant kinetics which is very slow at environmentally relevant APAP concentrations. Natural removal of APAP in the environment is limited by kinetics, therefore APAP-bearing waste streams should be treated in adsorption enhanced biological systems before discharged into the environment.


Assuntos
Acetaminofen/metabolismo , Biotransformação , Adsorção , Bactérias/metabolismo , Cinética , Poluentes do Solo/metabolismo , Poluentes Químicos da Água/metabolismo
15.
ACS Appl Mater Interfaces ; 11(42): 39179-39191, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31573786

RESUMO

Advances in personalized medicine will require custom drug formulations and delivery mechanisms. Herein, we demonstrate a new type of personalized capsule comprising of printed concentric cylindrical layers with each layer having a distinctive functional drug component. Poly ε-caprolactone (PCL) with paracetamol (APAP) and chlorpheniramine maleate (CM), synergistic drugs commonly used to alleviate influenza symptoms, are printed as an inner layer and outer layer, respectively, via microscaled electrohydrodynamic (EHD) printing. Polyvinylpyrrolidone (PVP) nanofibers are embedded as interlayers between the two printed PCL-drug layers using electrospinning (ES) techniques. The complete concentric cylindrical capsule with a 6 mm inner diameter and 15 mm length can be swallowed for oral drug delivery. After dissolution of the PVP interlayer, the capsule separates in two, with inner and outer capsules for continuous drug dosing and targeting. Imaging was achieved using a 3T MRI system which allowed temporal observations of the targeted release through the incorporation of nanoparticles (Fe3O4). The morphology and structure, chemical composition, mechanical properties, and biocompatibility of the capsules were studied in vitro. In summary, this new type of custom printed and electrospun capsule that enabled component separation, targeted drug release may advance personalized medicine via multidrug oral delivery.


Assuntos
Acetaminofen/química , Cápsulas/química , Clorfeniramina/química , Portadores de Fármacos/química , Impressão Tridimensional , Acetaminofen/metabolismo , Administração Oral , Animais , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Cápsulas/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Clorfeniramina/metabolismo , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Módulo de Elasticidade , Camundongos , Nanofibras/química , Poliésteres/química , Povidona/química
16.
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
17.
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
18.
Int J Numer Method Biomed Eng ; 35(9): e3234, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31254976

RESUMO

The spatial distributions of cytochrome P450 (CYP450) and glutathione (GSH) in liver lobules determine the heterogeneous hepatotoxicity of acetaminophen (APAP). Their interplay in conjunction with blood flow is not well understood. In this paper, we integrate a cellular APAP metabolism model with a sinusoidal blood flow to simulate the temporal-spatial patterns of APAP-induced hepatotoxicity. The heterogeneous distribution of CYP450 and GSH is modeled by linearly varying their reaction rates along the portal triad to the central vein axis of a sinusoid. We found that the spatial distribution of GSH, glutathione S-transferases (GSTs), and CYP450 all contributes to the high acetaminophen protein adduct formation at zone 3 of the lobules. The reversed spatial gradients of CYP450 and GSH cause quick depletion of GSH, which is further accelerated by the distribution of GST. The hepatic flow congestion and hyperperfusion however do not seem to play a significant role in the zonal hepatotoxicity. The simulation results may be useful for understanding the APAP-induced hepatotoxicity and associated pharmaceutical treatment.


Assuntos
Acetaminofen/metabolismo , Acetaminofen/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Modelos Biológicos , Analgésicos não Entorpecentes/administração & dosagem , Analgésicos não Entorpecentes/metabolismo , Analgésicos não Entorpecentes/toxicidade , Animais , Antipiréticos/administração & dosagem , Antipiréticos/metabolismo , Antipiréticos/toxicidade , Transporte Biológico Ativo , Engenharia Biomédica , Simulação por Computador , Sistema Enzimático do Citocromo P-450/metabolismo , Relação Dose-Resposta a Droga , Glutationa/metabolismo , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Circulação Hepática , Distribuição Tecidual
19.
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
20.
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
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