Asunto(s)
Acetaminofén , Enfermedad Hepática Inducida por Sustancias y Drogas , Acetaminofén/efectos adversos , Acetaminofén/farmacocinética , Acetaminofén/metabolismo , Acetaminofén/toxicidad , Humanos , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Analgésicos no Narcóticos/farmacocinética , Analgésicos no Narcóticos/efectos adversos , Analgésicos no Narcóticos/metabolismo , Animales , Hígado/metabolismo , Hígado/efectos de los fármacosRESUMEN
The mammalian gut microbiota plays diverse and essential roles in modulating host physiology. Key mediators determining the outcome of the microbiota-host interactions are the small molecule metabolites produced by the gut microbiota. The liver is a major organ exposed to gut microbial metabolites, and it serves as the nexus for maintaining healthy interactions between the gut microbiota and the host. At the same time, the liver is the primary target of potentially harmful gut microbial metabolites. In this review, we provide an up-to-date list of gut microbial metabolites that have been identified to either increase or decrease host susceptibility to acetaminophen (APAP)-induced liver injury. The signaling pathways and molecular factors involved in the progression of APAP-induced hepatotoxicity are well-established, and we propose that the mouse model of APAP-induced hepatotoxicity serves as a model system for uncovering gut microbial metabolites with previously unknown functions. Furthermore, we envision that gut microbial metabolites identified to alter APAP-induced hepatotoxicity likely have broader implications in other liver diseases. SIGNIFICANCE STATEMENT: This review provides an overview of the role of the gut microbiota in modulating the host susceptibility to acetaminophen (APAP)-induced liver injury. It focuses on the roles of gut bacterial small molecule metabolites as mediators of the interaction between the gut microbiota and the liver. It also illustrates the utility of APAP-induced liver injury as a model to identify gut microbial metabolites with biological function.
Asunto(s)
Acetaminofén , Enfermedad Hepática Inducida por Sustancias y Drogas , Microbioma Gastrointestinal , Acetaminofén/metabolismo , Acetaminofén/toxicidad , Acetaminofén/efectos adversos , Microbioma Gastrointestinal/efectos de los fármacos , Microbioma Gastrointestinal/fisiología , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Animales , Humanos , Hígado/metabolismo , Hígado/efectos de los fármacos , Ratones , Susceptibilidad a Enfermedades , Analgésicos no Narcóticos/toxicidad , Analgésicos no Narcóticos/metabolismo , Analgésicos no Narcóticos/efectos adversosRESUMEN
AIMS: Purinergic signaling-mediated mitochondria dysfunction and innate immune-mediated inflammation act as triggers during acetaminophen (APAP)-induced liver injury (AILI). However, the underlying mechanisms by which purinoceptor regulates mitochondria function and inflammation response in the progression of AILI remains unclear. METHODS: First, the hepatic level of purinergic receptor P2X 1 (P2RX1) was identified in the DILI patients and APAP-induced WT mice. P2rx1 knockout (KO) mice (P2rx1-/-) with 300 mg/kg APAP challenge were used for the analysis of the potential role of P2RX1 in the progression of AILI. Administration of DMX, the activator of stimulator of interferon genes (STING), was performed to investigate the effects of the STING-related pathway on APAP-treated P2rx1-/- mice. RESULTS: The elevated hepatic P2RX1 levels were found in DILI patients and the AILI mice. P2rx1 depletion offered protection against the initial stages of AILI, mainly by inhibiting cell death and promoting inflammation resolution, which was associated with alleviating mitochondria dysfunction. Mechanistically, P2rx1 depletion could inhibit STING-TANK-binding kinase 1 (TBK1)-P65 signaling pathways in vivo. We then showed that DMX-mediated STING activation could greatly aggravate the liver injury of P2rx1-/- mice treated with APAP. CONCLUSION: Our data confirmed that P2RX1 was inducted during AILI, identified P2RX1 as a novel regulator in mitochondria dysfunction and STING pathways, and suggested a promising therapeutic approach for AILI involving the blockade of P2RX1. 1. It first demonstrated the protective effects of P2rx1 deficiency on acetaminophen-induced liver injury (AILI). 2. P2rx1 knockout alleviates mitochondria function and promotes inflammation resolution after APAP treatment. 3. It first reported the regulation of P2RX1 on the STING signaling pathway in the progress of AILI. 4. P2RX1 blockade is a promising therapeutic strategy for AILI.
Asunto(s)
Analgésicos no Narcóticos , Enfermedad Hepática Crónica Inducida por Sustancias y Drogas , Enfermedad Hepática Inducida por Sustancias y Drogas , Fallo Hepático Agudo , Humanos , Animales , Ratones , Acetaminofén/efectos adversos , Analgésicos no Narcóticos/metabolismo , Enfermedad Hepática Crónica Inducida por Sustancias y Drogas/metabolismo , Hígado , Transducción de Señal , Fallo Hepático Agudo/metabolismo , Inflamación/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Ratones Endogámicos C57BLRESUMEN
Paracetamol or acetaminophen is the main non-opioid analgesic recommended for mild pain by the World Health Organization (WHO) analgesic ladder. However, the high levels used of paracetamol are associated with the hepatotoxicity and nephrotoxicity caused by accumulation of toxic metabolites. The sensor is produced on a polyester substrate containing a full electrochemical device with working, auxiliary, and reference electrodes in which, guiding personalized medicine solutions are not reported. Temporal paracetamol profiles in human saliva are performed with the subject taking different amounts of commercial analgesic pills. The variation of saliva paracetamol levels is demonstrated to be interference free from electroactive interfering species and human saliva constituents. In addition, the sensor displays to be useful as a disposable device for the fast detection of paracetamol in untreated raw saliva following pill intake. The maximum concentration (Cmax ) and half-life time (t1/2 ) for paracetamol are 143.27 µm and 110 min. The results demonstrate the potential of a simple strategy with electrochemical devices for noninvasive personalized therapy toward guiding drug interventions through tracking of active substance, detecting, and correcting insufficiency of absorption to meet individual needs avoiding overdoses, side effects, and intoxication.
Asunto(s)
Acetaminofén , Analgésicos no Narcóticos , Humanos , Acetaminofén/uso terapéutico , Medicina de Precisión , Saliva/metabolismo , Monitoreo de Drogas , Analgésicos no Narcóticos/metabolismo , Analgésicos no Narcóticos/uso terapéuticoRESUMEN
Acetaminophen, also known as N-acetyl-p-aminophenol (APAP), is commonly used as an antipyretic and analgesic agent. APAP overdose can induce hepatic toxicity, known as acetaminophen-induced liver injury (AILI). However, therapeutic doses of APAP can also induce AILI in patients with excessive alcohol intake or who are fasting. Hence, there is a need to understand the potential pathological mechanisms underlying AILI. In this review, we summarize three main mechanisms involved in the pathogenesis of AILI: hepatocyte necrosis, sterile inflammation, and hepatocyte regeneration. The relevant factors are elucidated and discussed. For instance, N-acetyl-p-benzoquinone imine (NAPQI) protein adducts trigger mitochondrial oxidative/nitrosative stress during hepatocyte necrosis, danger-associated molecular patterns (DAMPs) are released to elicit sterile inflammation, and certain growth factors contribute to liver regeneration. Finally, we describe the current potential treatment options for AILI patients and promising novel strategies available to researchers and pharmacists. This review provides a clearer understanding of AILI-related mechanisms to guide drug screening and selection for the clinical treatment of AILI patients in the future.
Asunto(s)
Analgésicos no Narcóticos , Enfermedad Hepática Crónica Inducida por Sustancias y Drogas , Enfermedad Hepática Inducida por Sustancias y Drogas , Acetaminofén/metabolismo , Acetaminofén/toxicidad , Analgésicos no Narcóticos/metabolismo , Analgésicos no Narcóticos/toxicidad , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Enfermedad Hepática Crónica Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Crónica Inducida por Sustancias y Drogas/patología , Humanos , Inflamación/metabolismo , Hígado/patología , Ratones , Ratones Endogámicos C57BL , Necrosis/inducido químicamente , Necrosis/metabolismo , Necrosis/patologíaRESUMEN
Acetaminophen (APAP) overdose is a common cause of drug-induced liver injury (DILI). Ferroptosis has been recently implicated in APAP-induced liver injury (AILI). However, the functional role and underlying mechanisms of mitochondria in APAP-induced ferroptosis are unclear. In this study, the voltage-dependent anion channel (VDAC) oligomerization inhibitor VBIT-12 and ferroptosis inhibitors were injected via tail vein in APAP-injured mice. Targeted metabolomics and untargeted lipidomic analyses were utilized to explore underlying mechanisms of APAP-induced mitochondrial dysfunction and subsequent ferroptosis. As a result, APAP overdose led to characteristic changes generally observed in ferroptosis. The use of ferroptosis inhibitor ferrostatin-1 (or UAMC3203) and iron chelator deferoxamine further confirmed that ferroptosis was responsible for AILI. Mitochondrial dysfunction, which is associated with the tricarboxylic acid cycle and fatty acid ß-oxidation suppression, may drive APAP-induced ferroptosis in hepatocytes. APAP overdose induced VDAC1 oligomerization in hepatocytes, and protecting mitochondria via VBIT-12 alleviated APAP-induced ferroptosis. Ceramide and cardiolipin levels were increased via UAMC3203 or VBIT-12 in APAP-induced ferroptosis in hepatocytes. Knockdown of Smpd1 and Taz expression responsible for ceramide and cardiolipin synthesis, respectively, aggravated APAP-induced mitochondrial dysfunction and ferroptosis in hepatocytes, whereas Taz overexpression protected against these processes. By immunohistochemical staining, we found that levels of 4-hydroxynonenal (4-HNE) protein adducts were increased in the liver biopsy samples of patients with DILI compared to that in those of patients with autoimmune liver disease, chronic viral hepatitis B, and non-alcoholic fatty liver disease (NAFLD). In summary, protecting mitochondria via inhibiting VDAC1 oligomerization attenuated hepatocyte ferroptosis by restoring ceramide and cardiolipin content in AILI.
Asunto(s)
Analgésicos no Narcóticos , Enfermedad Hepática Inducida por Sustancias y Drogas , Ferroptosis , Canal Aniónico 1 Dependiente del Voltaje/metabolismo , Acetaminofén/efectos adversos , Analgésicos no Narcóticos/metabolismo , Animales , Cardiolipinas/metabolismo , Ceramidas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Hepatocitos/metabolismo , Humanos , Hígado/patología , Ratones , Ratones Endogámicos C57BL , Mitocondrias/metabolismoRESUMEN
Full degradation of acetaminophen (paracetamol) in aqueous solution was investigated at room temperature through heterogeneous iron nano-structured as catalyst in this article. Iron Nano-structured was prepared through simple hydrothermal processes using Iron oxide (Fe2O3) as precursor. The catalytic activity of as prepared Nano-catalyst (NC) was investigated in the degradation of the acetaminophen as an environmental pollutant, commonly called paracetamol, under different operating parameters like pH, dosages of acetaminophen and dose of NC. Remarkable differences in IR spectra were observed after reaction which showed complete degradation of 15 ppm of Acetaminophen using 0.1 g of nano-structured with the recovery of NC followed by its activity four times with full catalytic performance.
Asunto(s)
Acetaminofén/análisis , Analgésicos no Narcóticos/análisis , Compuestos Férricos/administración & dosificación , Nanoestructuras/administración & dosificación , Contaminantes Químicos del Agua/análisis , Acetaminofén/metabolismo , Analgésicos no Narcóticos/metabolismo , Catálisis/efectos de los fármacos , Espectroscopía Infrarroja por Transformada de Fourier/métodos , Contaminantes Químicos del Agua/metabolismoRESUMEN
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.
Asunto(s)
Acetaminofén/metabolismo , Biodegradación Ambiental , Rhizobiaceae/aislamiento & purificación , Aguas del Alcantarillado/microbiología , Purificación del Agua/métodos , Acetaminofén/análogos & derivados , Acetaminofén/química , Analgésicos no Narcóticos/metabolismo , Biotransformación , Hidroquinonas/metabolismo , Cinética , Rhizobiaceae/metabolismo , Aguas Residuales/química , Contaminantes Químicos del Agua/químicaRESUMEN
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.
Asunto(s)
Acetaminofén/efectos adversos , Acetaminofén/metabolismo , Analgésicos no Narcóticos/efectos adversos , Analgésicos no Narcóticos/metabolismo , Antipiréticos/efectos adversos , Antipiréticos/metabolismo , Acetilcisteína , Anciano , Animales , Antiinflamatorios no Esteroideos/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Estrés del Retículo Endoplásmico/efectos de los fármacos , Femenino , Glutatión , Humanos , Masculino , Mitocondrias Hepáticas/efectos de los fármacos , Estrés Oxidativo , EmbarazoRESUMEN
BACKGROUND AND AIM: Hepatic phase I drug-metabolizing enzymes CYP2E1, CYP1A2 and CYP3A4 catalyze the biotransformation of Acetaminophen (APAP) and are important in the mediation of toxicity. The potential role of other hepatic and non-hepatic Phase I enzymes in APAP toxicity has not been established. METHODS: PCR array containing 84 genes involved in phase I drug metabolism was examined in subgroups of hospitalized children for APAP overdose, categorized as no toxicity (ALT ≤ 45 IU/L, n=5) and moderate toxicity (ALT ≥ 500 IU/L, n=5). RESULTS: Significant downregulation was observed for ALDH6A1, CYP4F12 and GZMB in the no toxicity subgroup and ALDH1A1, CYP27A1 and GZMB in the moderate toxicity subgroup. qRTPCR confirmed significant downregulation for ALDH1A1, CYP4F12, and GZMB. In-silico analysis identified GZMB 3'UTR to be a target of miR-378a-5p. Overexpression of miR-378a-5p reduced the luciferase activity of GZMB 3'UTR reporter plasmid reportedly by 50%. NK-92 cells transfected with the miR-378a-5p mimic extended the effect of APAP on GZMB protein expression compared to mimic controls. In addition, miR-378a-5p was significantly upregulated in blood samples of children with APAP overdose undergoing NAC treatment. CONCLUSION: Overall, our study suggests the presence of a novel signaling pathway, whereby miR- 378a-5p inhibits GZMB expression in children with APAP overdose.
Asunto(s)
Acetaminofén/farmacocinética , Acetaminofén/toxicidad , Analgésicos no Narcóticos/farmacocinética , Analgésicos no Narcóticos/toxicidad , Granzimas/metabolismo , MicroARNs/genética , Acetaminofén/metabolismo , Analgésicos no Narcóticos/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Niño , Citocromo P-450 CYP1A2/metabolismo , Citocromo P-450 CYP2E1/metabolismo , Citocromo P-450 CYP3A/metabolismo , Humanos , Inactivación Metabólica/genéticaRESUMEN
Acetaminophen (AP) is a popularly recommended over-the-counter analgesic-antipyretic in clinical use. However, the drug is handicapped by the occurrence of hepatotoxic insult following acute ingestion. Consequently, AP-induced hepatotoxicity is often implicated in accidental or suicidal overdose. In the current study, we investigated the potential of bioisosteric replacement of amide in AP with 1,2,3-triazoles in curbing AP-induced hepatotoxicity. The therapeutic utility of synthesized bioisosteres was established by careful tailoring and optimization of the synthetic methodology along with detailed toxicological testing of pharmacologically potent acetaminophen-triazole derivatives (APTDs). Along the same lines, we herein report a series of 17 novel APTDs synthesized via aromatic substitution using sodium azide, l-proline, and copper iodide followed by click reaction with substituted alkynes using copper sulfate and sodium ascorbate. Pharmacological evaluation of synthesized APTDs revealed that, out of the series of 17 compounds, 5a and 5e were found to be most efficacious in exerting anti-inflammatory, analgesic, and antipyretic activity in an animal model. Further toxicity studies documented that, in both acute and sub-acute toxicology, AP administration caused significant hepatotoxicity, which was found to be a consequence of ROS-mediated oxidative stress. Potent APTDs (5a and 5e), on the other hand, revealed no adverse event in both acute and sub-toxicological analyses. Median lethal dose (LD50) and no observed adverse effect level (NOAEL) values for 5a and 5e were found to be >1000 mg/kg and 2000 mg/kg, respectively. The human equivalent dose, defining the maximum safe concentration of a compound in a human's physiology, was found to be 27.68 mg/kg for the most potent APTDs (5a and 5e). Thus, it can be concluded that triazole incorporation into AP nucleus produced conjugates devoid of hepatotoxic manifestations, having the added advantage of anti-inflammatory efficacy along with analgesic and antipyretic potency.
Asunto(s)
Acetaminofén/farmacología , Amidas/farmacología , Analgésicos no Narcóticos/farmacología , Hígado/efectos de los fármacos , Triazoles/farmacología , Acetaminofén/química , Acetaminofén/metabolismo , Amidas/química , Amidas/metabolismo , Analgésicos no Narcóticos/química , Analgésicos no Narcóticos/metabolismo , Animales , Relación Dosis-Respuesta a Droga , Hígado/metabolismo , Estructura Molecular , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/análisis , Especies Reactivas de Oxígeno/metabolismo , Triazoles/química , Triazoles/metabolismoRESUMEN
BACKGROUND AND OBJECTIVE: Little is known about acetaminophen (paracetamol) pharmacokinetics during pregnancy. The aim of this study was to develop a physiologically based pharmacokinetic (PBPK) model to predict acetaminophen pharmacokinetics throughout pregnancy. METHODS: PBPK models for acetaminophen and its metabolites were developed in non-pregnant and pregnant women. Physiological and enzymatic changes in pregnant women expected to impact acetaminophen pharmacokinetics were considered. Models were evaluated using goodness-of-fit plots and by comparing predicted pharmacokinetic profiles with in vivo pharmacokinetic data. Predictions were performed to illustrate the average concentration at steady state (Css,avg) values, used as an indicator for efficacy, of acetaminophen achieved following administration of 1000 mg every 6 h. Furthermore, as a measurement of potential hepatotoxicity, the molar dose fraction of acetaminophen converted to N-acetyl-p-benzoquinone imine (NAPQI) was estimated. RESULTS: PBPK models successfully predicted the pharmacokinetics of acetaminophen and its metabolites in non-pregnant and pregnant women. Predictions resulted in the lowest Css,avg in the third trimester (median [interquartile range]: 4.5 [3.8-5.1] mg/L), while Css,avg was 6.7 [5.9-7.4], 5.6 [4.7-6.3], and 4.9 [4.1-5.5] mg/L in non-pregnant, first trimester, and second trimester populations, respectively. Assuming a constant raised cytochrome P450 2E1 activity throughout pregnancy, the molar dose fraction of acetaminophen converted to NAPQI was highest during the first trimester (median [interquartile range]: 11.0% [9.1-13.4%]), followed by the second (9.0% [7.5-11.0%]) and third trimester (8.2% [6.8-10.1%]), compared with non-pregnant women (7.7% [6.4-9.4%]). CONCLUSION: Acetaminophen exposure is lower in pregnant than in non-pregnant women, and is related to pregnancy duration. Despite these findings, higher dose adjustments cannot be advised yet as it is unknown whether pregnancy affects the toxicodynamics of NAPQI. Information on glutathione abundance during pregnancy and NAPQI in vivo data are required to further refine the presented model.
Asunto(s)
Acetaminofén/farmacocinética , Benzoquinonas/farmacocinética , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Iminas/farmacocinética , Tercer Trimestre del Embarazo/metabolismo , Acetaminofén/administración & dosificación , Acetaminofén/metabolismo , Acetaminofén/toxicidad , Adulto , Analgésicos no Narcóticos/administración & dosificación , Analgésicos no Narcóticos/metabolismo , Analgésicos no Narcóticos/farmacocinética , Analgésicos no Narcóticos/toxicidad , Arilsulfotransferasa/metabolismo , Benzoquinonas/administración & dosificación , Benzoquinonas/metabolismo , Benzoquinonas/toxicidad , Simulación por Computador , Citocromo P-450 CYP2E1/metabolismo , Femenino , Glucuronosiltransferasa/metabolismo , Glutatión/metabolismo , Humanos , Iminas/administración & dosificación , Iminas/metabolismo , Iminas/toxicidad , EmbarazoRESUMEN
Dissolution testing plays many important roles throughout the pharmaceutical industry, from the research and development of drug products to the control and evaluation of drug quality. However, it is a challenging task to perform both high-efficient separation and high-temporal detection to achieve accurate dissolution profile of each active ingredient dissolved from a drug tablet. In our study, we report a novel non-manual-operation method for performing the automatic dissolution testing of drug tablets, by combining a program-controlled sequential analysis and high-speed capillary electrophoresis for efficient separation of active ingredients. The feasibility of the method for dissolution testing of real drug tablets as well as the performance of the proposed system has been demonstrated. The accuracy of drug dissolution testing is ensured by the excellent repeatability of the sequential analysis, as well as the similarity of the evaluation of dissolution testing. Our study show that the proposed method is capable to achieve simultaneous dissolution testing of multiple ingredients, and the matrix interferences can be avoided. Therefore it is of potential valuable applications in various fields of pharmaceutical research and drug regulation.
Asunto(s)
Acetaminofén/metabolismo , Química Farmacéutica , Clorzoxazona/metabolismo , Liberación de Fármacos , Control de Calidad , Comprimidos/química , Acetaminofén/química , Analgésicos no Narcóticos/química , Analgésicos no Narcóticos/metabolismo , Automatización , Clorzoxazona/química , Combinación de Medicamentos , Humanos , Relajantes Musculares Centrales/química , Relajantes Musculares Centrales/metabolismo , SolubilidadRESUMEN
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.
Asunto(s)
Acetaminofén/metabolismo , Acetaminofén/toxicidad , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Modelos Biológicos , Analgésicos no Narcóticos/administración & dosificación , Analgésicos no Narcóticos/metabolismo , Analgésicos no Narcóticos/toxicidad , Animales , Antipiréticos/administración & dosificación , Antipiréticos/metabolismo , Antipiréticos/toxicidad , Transporte Biológico Activo , Ingeniería Biomédica , Simulación por Computador , Sistema Enzimático del Citocromo P-450/metabolismo , Relación Dosis-Respuesta a Droga , Glutatión/metabolismo , Humanos , Hígado/efectos de los fármacos , Hígado/metabolismo , Circulación Hepática , Distribución TisularRESUMEN
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.
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Acetaminofén/metabolismo , Arilsulfotransferasa/genética , Naproxeno/análogos & derivados , Tapentadol/metabolismo , Analgésicos no Narcóticos/metabolismo , Analgésicos Opioides/metabolismo , Citosol/metabolismo , Escherichia coli/citología , Genotipo , Humanos , Isoenzimas , Mutagénesis Sitio-Dirigida , Naproxeno/metabolismo , Polimorfismo de Nucleótido Simple , Sulfatos/metabolismoRESUMEN
Acetaminophen (APAP)-induced liver injury is clinically significant, and APAP overdose in mice often serves as a model for drug-induced liver injury in humans. By specifying that APAP metabolism, reactive metabolite formation, glutathione depletion, and mitigation of mitochondrial damage within individual hepatocytes are functions of intralobular location, an earlier virtual model mechanism provided the first concrete multiattribute explanation for how and why early necrosis occurs close to the central vein (CV). However, two characteristic features could not be simulated consistently: necrosis occurring first adjacent to the CV, and subsequent necrosis occurring primarily adjacent to hepatocytes that have already initiated necrosis. We sought parsimonious model mechanism enhancements that would manage spatiotemporal heterogeneity sufficiently to enable meeting two new target attributes and conducted virtual experiments to explore different ideas for model mechanism improvement at intrahepatocyte and multihepatocyte levels. For the latter, evidence supports intercellular communication via exosomes, gap junctions, and connexin hemichannels playing essential roles in the toxic effects of chemicals, including facilitating or counteracting cell death processes. Logic requiring hepatocytes to obtain current information about whether downstream and lateral neighbors have triggered necrosis enabled virtual hepatocytes to achieve both new target attributes. A virtual hepatocyte that is glutathione-depleted uses that information to determine if it will initiate necrosis. When a less-stressed hepatocyte is flanked by at least two neighbors that have triggered necrosis, it too will initiate necrosis. We hypothesize that the resulting intercellular communication-enabled model mechanism is analogous to the actual explanation for APAP-induced hepatotoxicity at comparable levels of granularity.
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Acetaminofén/toxicidad , Analgésicos no Narcóticos/toxicidad , Comunicación Celular/efectos de los fármacos , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Hepatocitos/efectos de los fármacos , Modelos Biológicos , Biología de Sistemas , Acetaminofén/metabolismo , Activación Metabólica , Analgésicos no Narcóticos/metabolismo , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Simulación por Computador , Glutatión/metabolismo , Hepatocitos/metabolismo , Hepatocitos/patología , Masculino , Ratones Endogámicos C57BL , Necrosis , Transducción de Señal , Factores de TiempoRESUMEN
Children undergoing cardiac surgery often receive acetaminophen (paracetamol) as part of their postoperative pain treatment. To date, there is no information on the pharmacokinetics (PK) of acetaminophen in this special population, even though differences, as a result of altered hemodynamics and/or use of cardiopulmonary bypass, may be anticipated. Therefore, the aim of this study was to investigate the PK of intravenous acetaminophen in children after cardiac surgery with cardiopulmonary bypass. In the study, both children with and without Down syndrome were included. A population PK analysis, using NONMEM 7.2, was performed based on 161 concentrations of acetaminophen, acetaminophen sulfate, acetaminophen glucuronide, and oxidative metabolites from 17 children with Down syndrome and 13 children without Down syndrome of a previously published study (median age, 177 days [range, 92-944], body weight, 6.1 kg [4.0-12.9]). All children received 3 intravenous acetaminophen doses of 7.5 mg/kg (<10 kg) or 15 mg/kg (≥10 kg) at 8-hour intervals after cardiac surgery. For acetaminophen and its metabolites, 1-compartment models were identified. Clearance of acetaminophen and metabolites increased linearly with body weight. Acetaminophen clearance in a typical child of 6.1 kg is 0.96 L/h and volume of distribution 7.96 L. Down syndrome did not statistically significantly impact any of the PK parameters for acetaminophen, nor did any other remaining covariate. When comparing the PK parameters of acetaminophen in children after cardiac surgery with cardiopulmonary bypass with those from children of the same age following noncardiac surgery reported in the literature, clearance of acetaminophen was lower and volume of distribution higher.
Asunto(s)
Acetaminofén/metabolismo , Acetaminofén/farmacocinética , Analgésicos no Narcóticos/metabolismo , Analgésicos no Narcóticos/farmacocinética , Dolor Postoperatorio/tratamiento farmacológico , Acetaminofén/administración & dosificación , Administración Intravenosa , Analgésicos no Narcóticos/administración & dosificación , Variación Biológica Poblacional/efectos de los fármacos , Peso Corporal , Procedimientos Quirúrgicos Cardíacos , Puente Cardiopulmonar , Preescolar , Síndrome de Down , Femenino , Humanos , Lactante , Infusiones Intravenosas , Masculino , Tasa de Depuración Metabólica , Modelos Biológicos , Estudios ProspectivosRESUMEN
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.
Asunto(s)
Aves/genética , Regulación Enzimológica de la Expresión Génica/fisiología , Glucuronosiltransferasa/metabolismo , Acetaminofén/metabolismo , Analgésicos no Narcóticos/metabolismo , Animales , Aves/metabolismo , Glucuronosiltransferasa/genética , Microsomas Hepáticos/enzimología , Filogenia , Especificidad de la Especie , SinteníaRESUMEN
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.
Asunto(s)
Acetaminofén/metabolismo , Contaminantes Ambientales/metabolismo , Hígado/enzimología , Filogenia , Proteínas de Reptiles/metabolismo , Serpientes/fisiología , Acetaminofén/efectos adversos , Acetaminofén/toxicidad , Acetiltransferasas/genética , Acetiltransferasas/metabolismo , Agkistrodon/genética , Agkistrodon/fisiología , Analgésicos no Narcóticos/efectos adversos , Analgésicos no Narcóticos/metabolismo , Animales , Biotransformación , Boidae/genética , Boidae/fisiología , Colubridae/genética , Colubridae/fisiología , Crotalus/genética , Crotalus/fisiología , Bases de Datos Genéticas , Resistencia a Medicamentos , Contaminantes Ambientales/toxicidad , Glucuronosiltransferasa/genética , Glucuronosiltransferasa/metabolismo , Glutatión Transferasa/genética , Glutatión Transferasa/metabolismo , Isoenzimas/genética , Isoenzimas/metabolismo , Proteínas de Reptiles/genética , Serpientes/genética , Especificidad de la Especie , Sulfotransferasas/genética , Sulfotransferasas/metabolismo , ToxicocinéticaRESUMEN
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 5â¯mgâ¯L-1 acetaminophen for 144â¯h, GSH-acetaminophen conjugates were 15.2⯱â¯1.3â¯nmolâ¯g-1 and 1.2⯱â¯0.1â¯nmolâ¯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 48â¯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.