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Toxic Metabolites (toxic + metabolite)
Selected AbstractsAlcohol exposure and paracetamol-induced hepatotoxicityADDICTION BIOLOGY, Issue 2 2002STEPHEN M. RIORDAN In contrast, serious hepatotoxicity at recommended or near-recommended doses for therapeutic purposes has been reported, mainly from the United States and in association with chronic alcohol use, leading to the widely held belief that chronic alcoholics are predisposed to paracetamol-related toxicity at relatively low doses. Yet the effects of alcohol on paracetamol metabolism are complex. Studies performed in both experimental animals and humans indicate that chronic alcohol use leads to a short-term, two- to threefold increase in hepatic content of cytochrome P4502E1, the major isoform responsible for the generation of the toxic metabolite from paracetamol, although increased oxidative metabolism of paracetamol at recommended doses has not been demonstrated clinically. A reduced hepatic content of glutathione, required to detoxify the reactive metabolite, has been documented in chronic alcoholics, due probably to associated fasting and malnutrition, providing a metabolic basis for any possible predisposition of this group to hepatotoxicity at relatively low paracetamol doses. Simultaneous alcohol and paracetamol ingestion reduces oxidative metabolism of paracetamol in both rodents and humans, predominantly as a consequence of depletion in cytosol of free NADPH. The possibilities that chronic alcohol use may predispose to paracetamol-related hepatotoxicity and that alcohol taken with paracetamol may protect against it, based on these metabolic observations, are examined in this review. [source] Michaelis-Menten Elimination Kinetics of Acetaldehyde During Ethanol OxidationALCOHOLISM, Issue 2002Tatsuya Fujimiya Background Acetaldehyde (AcH) is a toxic metabolite of ethanol (EtOH). The pharmacokinetics of blood AcH during EtOH oxidation was studied with or without the administration of aldehyde dehydrogenase 2 inhibitor (cyanamide) in rabbits. Methods An bolus of EtOH saline solution (0.25, 0.5, 1.0, 1.5, and 2.0 g/kg) was injected intravenously. Cyanamide was administered intraperitoneally (25 mg/kg body weight) to the cyanamide-treated group. Blood EtOH and AcH concentrations were measured by using head-space gas chromatography. Results In the control group, the first peak of the blood AcH appeared immediately and the second elevation appeared 1 to 4 hr after administration at a high EtOH dose. The blood AcH levels other than the second elevation part were significantly correlated to the blood EtOH levels. In the cyanamide-treated group, a peak and a plateau formed at the time corresponding to the second peak in the control group. The peak and plateau concentration of AcH increased markedly. We attempted simultaneous curve fitting, using the five blood EtOH and AcH concentration-time curves, to determine the pharmacokinetic model. Consequently, the AcH elimination was best described by a Michaelis-Menten kinetic model in both groups. Conclusions The blood AcH profile was suggested to consist of the first and second components that are related to the blood EtOH concentration itself and the metabolic formation of AcH, respectively. With higher EtOH doses or aldehyde dehydrogenase 2 inhibition, the second component becomes prominent as a result of the capacity-limited property of the metabolism of AcH, which is described by Michaelis-Menten elimination kinetics. [source] Prevalence of the MspI and Ile462Val SNPs of Cytochrome P-450 1A1 in Hidradenitis SuppurativaEXPERIMENTAL DERMATOLOGY, Issue 6 2010Ansgar Lukowsky Please cite this paper as: Prevalence of the MspI and Ile462Val SNPs of Cytochrome P-450 1A1 in Hidradenitis Suppurativa. Experimental Dermatology 2010; 19: 541,542. Abstract:, Hidradenitis Suppurativa (HS) is a chronic inflammatory skin disease that affects the hair follicles in the axillary, perianal and inguinal area. Its cause and pathogenesis are unknown, but cigarette smoking increases the risk of developing HS conceivably by accumulating toxic metabolites in sweat. The xenobiotic compounds from tobacco are metabolized by the cytochromes P-450. The cytochrome P-450 1A1 (CYP1A1), one of the most active isoenzymes, harbours several polymorphisms. Two of them, MspI and Ile462Val single nucleotide polymorphism (SNP), are associated with enhanced activity and inducibility. Performing direct DNA sequencing, we investigated the frequencies of these SNP in 51 patients with HS, 45 of these were smokers. We found similar overall SNP rates in our patients in comparison with previous data for Caucasian or German controls. Obviously, there is no relation between the occurrence of these SNPs and the risk of developing HS. [source] Multidrug resistance,associated proteins are crucial for the viability of activated rat hepatic stellate cells,,HEPATOLOGY, Issue 2 2008Rebekka A. Hannivoort Hepatic stellate cells (HSCs) survive and proliferate in the chronically injured liver. ATP-binding cassette (ABC) transporters play a crucial role in cell viability by transporting toxic metabolites or xenobiotics out of the cell. ABC transporter expression in HSCs and its relevance to cell viability and/or activation have not been reported so far. The aim of this study was to investigate the expression, regulation, and function of multidrug resistance,associated protein (Mrp)-type and multidrug resistance protein (Mdr),type ABC transporters in activated rat HSCs. Rat HSCs were exposed to cytokines or oxidative stress. ABC transporter expression was determined by quantitative polymerase chain reaction and immunohistochemistry. HSCs were exposed to the Mdr inhibitors verapamil and PSC-833 and the Mrp inhibitor MK571. Mdr and Mrp transporter function was evaluated with flow cytometry. Apoptosis was determined by activated caspase-3 and acridine orange staining, and necrosis was determined by Sytox green nuclear staining. An in vivo model of carbon tetrachloride (CCl4),induced liver fibrosis was used. With respect to hepatocytes, activated HSCs expressed high levels of Mrp1 and comparable levels of Mrp3, Mrp4, Mdr1a, and Mdr1b but not the hepatocyte-specific transporters bile salt export pump, Mrp2, and Mrp6. Mrp1 protein staining correlated with desmin staining in livers from CCl4 -treated rats. Mrp1 expression increased upon activation of HSCs. Cytokines induced Mdr1b expression only. Oxidative stress was not a major regulator of Mdr and Mrp transporter expression. Activated HSCs became necrotic when exposed to the Mrp inhibitors. Conclusion: Activated HSCs contain relatively high levels of Mrp1. Mrp-type transporters are required for the viability of activated HSCs. Mrp-dependent export of endogenous metabolites is important for the survival of activated HSCs in chronic liver diseases. (HEPATOLOGY 2008.) [source] Molecular characterization of a prophenoloxidase cDNA from the malaria mosquito Anopheles stephensiINSECT MOLECULAR BIOLOGY, Issue 2 2000L. Cui Abstract Some refractory anopheline mosquitoes are capable of killing Plasmodium, the causative agent of malaria, by melanotic encapsulation of invading ookinetes. Phenoloxidase (PO) appears to be involved in the formation of melanin and toxic metabolites in the surrounding capsule. A cDNA encoding Anopheles stephensi prophenoloxidase (Ans-proPO) was isolated from a cDNA library screened with an amplimer produced by reverse transcriptase polymerase chain reaction (RT-PCR) with degenerate primers designed against conserved proPO sequences. The 2.4-kb-long cDNA has a 2058 bp open reading frame encoding Ans-proPO of 686 amino acids. The deduced amino acid sequence shows significant homology to other insect proPO sequences especially at the two putative copper-binding domains. In A. stephensi, Ans-proPO expression was detected in larval, pupal and adult stages. The Ans-proPO mRNA was detected by RT-PCR and in situ hybridization in haemocytes, fat body and epidermis of adult female mosquitoes. A low level of expression was detected in the ovaries, whereas no expression was detected in the midguts. Semi-quantitative RT-PCR analysis of Ans-proPO mRNA showed that its expression was similar in adult female heads, thoraxes and abdomens. No change in the level of Ans-proPO expression was found in adult females after blood feeding, bacterial challenge or Plasmodium berghei infection. However, elevated PO activity was detected in P. berghei -infected mosquitoes, suggesting that in non-selected permissive mosquitoes PO may be involved in limiting parasite infection. Genomic Southern blot and immunoblots suggest the presence of more than one proPO gene in the A. stephensi genome, which is consistent with the findings in other Diptera and Lepidoptera species. The greatest similarity in sequence and expression profile between Ans-proPO and A. gambiae proPO6 suggests that they might be homologues. Our results demonstrate that Ans-proPO is constitutively expressed through different developmental stages and under different physiological conditions, implying that other factors in the proPO activation cascade regulate melanotic encapsulation. [source] Safety of pyrethroid-treated mosquito netsMEDICAL AND VETERINARY ENTOMOLOGY, Issue 1 2000M. Zaim Summary The use of insecticide treated nets (ITNs) for personal protection against malaria vector Anopheles mosquitoes (Diptera: Culicidae) has become popular during the past decade. With the precautions outlined in this paper, field use of pyrethroids , at concentrations recommended for treatment of mosquito nets , poses little or no hazard to people treating the nets or to users of the treated nets. With frequent exposure to low concentrations of pyrethroids, the risk of toxicity of any kind is remote. Pyrethroids entering the systemic circulation are rapidly metabolized to much less toxic metabolites. Toxicologically, pyrethroids have a useful characteristic , the production of skin paraesthesia , which gives an early indication of exposure. This reversible symptom of exposure is due to transient stimulation of peripheral sensory nerves and not a toxic effect. In the retail market, for home use, the provision of proper packaging and labelling, with clear instructions on safe and effective use of the product are most important. Because many domestic users of pyrethroid ,home treatment kits' for ITNs may not be fully literate, it is essential that ,instructions for use' should be portrayed via pictograms with supporting text in appropriate local language(s). [source] Medicinal chemistry approaches for the treatment and prevention of Alzheimer's diseaseMEDICINAL RESEARCH REVIEWS, Issue 1 2003S.O. Bachurin Abstract Alzheimer's disease (AD) is the most common form of dementia, which is characterised by progressive deterioration of memory and higher cortical functions that ultimately result in total degradation of intellectual and mental activities. Modern strategies in the search of new therapeutic approaches are based on the morphological and biochemical characteristics of AD, and focused on following directions: agents that compensate the hypofunction of cholinergic system, agents that interfere with the metabolism of beta-amyloid peptide, agents that protect nerve cells from toxic metabolites formed in neurodegenerative processes, agents that activate other neurotransmitter systems that indirectly compensate for the deficit of cholinergic functions, agents that affect the process of the formation of neurofibrillary tangles, anti-inflammatory agents that prevent the negative response of nerve cells to the pathological process. The goal of the present review is the validation and an analysis from the point of view of medicinal chemistry of the principles of the directed search of drugs for the treatment and prevention of AD and related neurodegenerative disorders. It is based on systematization of the data on biochemical and structural similarities in the interaction between physiologically active compounds and their biological targets related to the development of such pathologies. The main emphasis is on cholinomimetic, anti-amyloid and anti-metabolic agents, using the data that were published during the last 3 to 4 years, as well as the results of clinical trials presented on corresponding websites. © 2002 Wiley Periodicals, Inc. Med Res Rev, 23, No. 1, 48,88, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/med.10026 [source] Role of drug metabolism in drug discovery and developmentMEDICINAL RESEARCH REVIEWS, Issue 5 2001Gondi N. Kumar Abstract Metabolism by the host organism is one of the most important determinants of the pharmacokinetic profile of a drug. High metabolic lability usually leads to poor bioavailability and high clearance. Formation of active or toxic metabolites will have an impact on the pharmacological and toxicological outcomes. There is also potential for drug,drug interactions with coadministered drugs due to inhibition and/or induction of drug metabolism pathways. Hence, optimization of the metabolic liability and drug,drug interaction potential of the new chemical entities are some of the most important steps during the drug discovery process. The rate and site(s) of metabolism of new chemical entities by drug metabolizing enzymes are amenable to modulation by appropriate structural changes. Similarly, the potential for drug,drug interactions can also be minimized by appropriate structural modifications to the drug candidate. However, the optimization of the metabolic stability and drug,drug interaction potential during drug discovery stage has been largely by empirical methods and by trial and error. Recently, a lot of effort has been applied to develop predictive methods to aid the optimization process during drug discovery and development. This article reviews the role of drug metabolism in drug discovery and development. © 2001 John Wiley & Sons, Inc. Med Res Rev, 21, No. 5, 397,411, 2001 [source] Effect of Transvenous Cardiac Resynchronization Therapy Device Implantation on Cardiac Troponin I ReleasePACING AND CLINICAL ELECTROPHYSIOLOGY, Issue 11 2007TIMUCIN ALTIN M.D. Background: Pacemaker and implantable cardioverter defibrillator (ICD) implantation increases cardiac troponin I (cTnI) levels which indicates myocardial injury. During implantation of a cardiac resynchronization therapy (CRT) device, balloon inflation for coronary sinus (CS) venogram, cannulation of CS side branch, and electrode advancement may interfere with CS drainage and, hence, may decrease the washout of toxic metabolites from the heart. Thus, CRT implantation may further increase cTnI levels. In this study, we investigated the effects of CRT implantation on cTnI release. Methods: We included 10 patients (mean age = 57 ± 15 years) in whom a successful transvenous CRT system was implanted (CRT group). Twenty patients (mean age = 65 ± 10 years) who underwent a transvenous pacemaker or ICD implantation were included as the control group. Blood samples for cTnI were drawn at baseline and at six, 12, 18, and 24 hours thereafter. Results: Baseline median cTnI levels were similar in CRT and control groups (0.03 ng/mL vs 0.02 ng/mL, respectively; P = 0.1). Postoperative cTnI levels during 24 hours were significantly higher in the CRT group (P < 0.05) by two-way repeated measures of analyis of variance. Post hoc analysis revealed that cTnI levels were higher at the 6th, 12th, 18th, and 24th hours compared to baseline levels (P < 0.001, P < 0.001, P < 0.01, and P < 0.01, respectively). There was a significant difference in the area under the curves (AUCs) of cTnI measurements (1.79 hr·ng/mL in the CRT group and 0.78 hr·ng/mL in the control group, P < 0.05). Conclusion: Postoperative cTnI levels were higher after CRT implantation than simple pacemaker/ICD implantation. This may be due to CS manipulation during CRT implantation. [source] Loss of heterozygosity of DNA repair gene, hOGG1, in renal cell carcinoma but not in renal papillary adenomaPATHOLOGY INTERNATIONAL, Issue 6 2008Neriman Gokden The kidney is constantly exposed to free radicals due to its active metabolism and processing of toxic metabolites. Among 20 or so free radical-induced DNA lesions, 8-oxoquanine is the most abundant and is potentially mutagenic if not sufficiently removed. The human 8-oxoquanine DNA glycosylase 1 (hOGG1) gene repairs 8-oxoguanine and resides at 3p25,26, which has frequent loss of heterozygosity (LOH) in clear cell,renal cell carcinoma (CC-RCC). Even though some studies found similar genetic alterations between renal papillary adenomas (PA) and papillary RCC (PRCC), no studies have been conducted to compare the alterations of hOGG1 gene in PA, PRCC and CC-RCC. To further explore the relationship between CC-RCC, PRCC and PA at the genetic level LOH of hOGG1 gene was investigated in these three groups. It was found that 8/8 PRCC (100%) and 8/9 CC-RCC (88%) had evidence of hOGG1 LOH, whereas all four PA (0%) were devoid of hOGG1 LOH. It is concluded that deletion of hOGG1 gene occurs commonly in PRCC and CC-RCC but not in renal cortical PA. Further studies are warranted to further explore the exact roles of hOGG1 gene in the development and progression of RCC. [source] Increasing throughput and information content for in vitro drug metabolism experiments using ultra-performance liquid chromatography coupled to a quadrupole time-of-flight mass spectrometerRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 6 2005Jose Castro-Perez The field of drug metabolism has been revolutionized by liquid chromatography/mass spectrometry (LC/MS) applications with new technologies such as triple quadrupoles, ion traps and time-of-flight (ToF) instrumentation. Over the years, these developments have often relied on the improvements to the mass spectrometer hardware and software, which has allowed users to benefit from lower levels of detection and ease-of-use. One area in which the development pace has been slower is in high-performance liquid chromatography (HPLC). In the case of metabolite identification, where there are many challenges due to the complex nature of the biological matrices and the diversity of the metabolites produced, there is a need to obtain the most accurate data possible. Reactive or toxic metabolites need to be detected and identified as early as possible in the drug discovery process, in order to reduce the very costly attrition of compounds in late-phase development. High-resolution, exact mass measurement plays a very important role in metabolite identification because it allows the elimination of false positives and the determination of non-trivial metabolites in a much faster throughput environment than any other standard current methodology available to this field. By improving the chromatographic resolution, increased peak capacity can be achieved with a reduction in the number of co-eluting species leading to superior separations. The overall enhancement in the chromatographic resolution and peak capacity is transferred into a net reduction in ion suppression leading to an improvement in the MS sensitivity. To investigate this, a number of in vitro samples were analyzed using an ultra-performance liquid chromatography (UPLC) system, with columns packed with porous 1.7,,m particles, coupled to a hybrid quadrupole time-of-flight (ToF) mass spectrometer. This technique showed very clear examples for fundamental gains in sensitivity, chromatographic resolution and speed of analysis, which are all important factors for the demands of today's HTS in discovery. Copyright © 2005 John Wiley & Sons, Ltd. [source] Therapeutic effect of exosomes from indoleamine 2,3-dioxygenase,positive dendritic cells in collagen-induced arthritis and delayed-type hypersensitivity disease modelsARTHRITIS & RHEUMATISM, Issue 2 2009Nicole R. Bianco Objective We have demonstrated previously that dendritic cells (DCs) modified with immunosuppressive cytokines, and exosomes derived from DCs can suppress the onset of murine collagen-induced arthritis (CIA) and reduce the severity of established arthritis. Indoleamine 2,3-dioxygenase (IDO) is a tryptophan-degrading enzyme that is important for immune regulation and tolerance maintenance. DCs expressing functional IDO can inhibit T cells by depleting them of essential tryptophan and/or by producing toxic metabolites, as well as by generating Treg cells. This study was undertaken to examine the immunosuppressive effects of bone marrow (BM),derived DCs genetically modified to express IDO, and of exosomes derived from IDO-positive DCs. Methods BM-derived DCs were adenovirally transduced with IDO or CTLA-4Ig (an inducer of IDO), and the resulting DCs and exosomes were tested for their immunosuppressive ability in the CIA and delayed-type hypersensitivity (DTH) murine models. Results Both DCs and exosomes derived from DCs overexpressing IDO had an antiinflammatory effect in CIA and DTH murine models. The suppressive effects were partially dependent on B7 costimulatory molecules. In addition, gene transfer of CTLA-4Ig to DCs resulted in induction of IDO in the DCs and in exosomes able to reduce inflammation in an IDO-dependent manner. Conclusion These results demonstrate that both IDO-expressing DCs and DC-derived exosomes are immunosuppressive and antiinflammatory, and are able to reverse established arthritis. Therefore, exosomes from IDO-positive DCs may represent a novel therapy for rheumatoid arthritis. [source] Activity of NADPH-Cytochrome P-450 Reductase of the Human Heart, Liver and Lungs in the Presence of (-)-Epigallocatechin Gallate, Quercetin and Resveratrol: An in vitro StudyBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 2 2005Jaroslaw Dudka The enzyme is also involved in the toxicity of some clinically important antitumour drugs (doxorubicin) and pesticides (paraquat). P-450 reductase activates them to their more toxic metabolites via one electron reduction which triggers free radical cascade. In some cases however, such transformation is essential to produce therapeutic effect in anticancer drugs. The main purpose of the paper was to evaluate the effect of three natural compounds found in human diet: (-)-epigallocatechin gallate (EGCG), quercetin and resveratrol on P-450 reductase activity. The activity of the enzyme was determined spectrophotometrically by measurement of the rate of cytochrome c reduction at 550 nm, in vitro, using human heart, liver and lung microsomes. It was found that quercetin increased the P-450 reductase activity in human organs at all tested doses. The activity of microcosms in all organs was enhanced according to the concentrations of quercetin, which increased the activity in the order lung>heart>liver. Addition of EGCG to the reaction mixture enhanced the P-450 reductase activity in the following order: liver>heart>lung. However, no significant effect of resveratrol on P-450 reductase activity was observed. It seems that the presence of quercetin and EGCG in the diet may increase P-450 reductase activity during doxorubicin therapy with subsequent increased risk of toxicity. A beneficial effect may be obtained in anticancer therapy with bioreductive agents like tirapazamine. [source] Influence of the prodrugs 5-fluorocytosine and CPT-11 on ovarian cancer cells using genetically engineered stem cells: tumor-tropic potential and inhibition of ovarian cancer cell growthCANCER SCIENCE, Issue 4 2010Ki-Yon Kim Recent studies have shown that genetically engineered stem cells (GESTECs) to produce suicide enzymes that convert non-toxic prodrugs to toxic metabolites selectively migrate toward tumor sites and reduce tumor growth. In the present study, we evaluated whether these GESTECs were capable of migrating to human ovarian cancer cells and examined the potential therapeutic efficacy of the gene-directed enzyme prodrug therapy against ovarian cancer cells in vitro. The expression of cytosine deaminase (CD) or carboxyl esterase (CE) mRNA of GESTECs was confirmed by RT-PCR. A modified transwell migration assay was performed to determine the migratory capacity of GESTECs to ovarian cancer cells. GESTECs (HB1.F3.CD or HB1.F3.CE cells) engineered to express a suicide gene (CD or CE) selectively migrated toward ovarian cancer cells. A [3H] thymidine incorporation assay was conducted to measure the proliferative index. Treatment of human epithelial ovarian cancer cell line (SKOV-3, an ovarian adenocarcinoma derived from the ascites of an ovarian cancer patient) with the prodrugs 5-fluorocytosine (5-FC) or camptothecin-11 (CPT-11) in the presence of HB1.F3.CD or HB1.F3.CE cells resulted in the inhibition of ovarian cancer cell growth. Based on the data presented herein, we suggest that GESTECs expressing CD/CE may have a potent advantage to selectively treat ovarian cancers. (Cancer Sci 2010; 101: 955,962) [source] | ||||||||||||||||