Urothelial neoplasia with plasmacytoid morphology.
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Aged↗
Biomedical subjects
E Sim
Publications and source records attributed to E Sim.
Structure and mechanism of arylamine N-acetyltransferases.
Arylamine N-acetyltransferases (NATs) are a family of phase II drug-metabolising enzymes which are important in the biotransformation of various aromatic and heterocyclic amines and hydroxylamines, arylhydrazines and arylhydrazides. NATs are present in a wide range of eukaryotes and prokaryotes. Humans have two functional NAT isoforms, both of which are highly polymorphic. The pharmacogenetics of NATs is an area which has been extensively studied. The determination of the X-ray crystal structure of NAT from Salmonella typhimurium led to the identification of the catalytically essential triad of residues: Cys-His-Asp, which is present in all functional NAT enzymes. Recent co-crystallisation data and in silico docking studies of NAT from Mycobacterium smegmatis with substrates and inhibitors have aided the identification of important contact residues within the active site. The X-ray crystal structures of four prokaryotic NAT proteins have now been determined, and these have been used to generate structural models of eukaryotic NATs, providing valuable insight into their active-site architecture. In addition to aiding crystallographic experiments, recent progress in the production of recombinant prokaryotic and eukaryotic NATs has allowed comparative studies of the kinetics and activity profiles of these enzymes. In this review we present an overview of recent structural and activity studies on NAT enzymes, and we outline how in silico methods may be used to predict NAT protein-ligand interactions based on the current knowledge.
Animals↗
Human VEGF165-myoblasts produce concomitant angiogenesis/myogenesis in the regenerative heart.
Bioengineering the regenerative heart may provide a novel treatment for heart failure. On May 14, 2002, a 55-year-old man suffering from ischemic myocardial infarction received 25 injections carrying 465 million cGMP-produced pure myoblasts into his myocardium after coronary artery bypass grafting. As on August 28, 2002, his EKG was normal and showed no arrhythmia. His ejection fraction increased by 13%. He no longer experienced shortness of breath and angina as he did before the treatment. Three myogenesis mechanisms were elucidated with 17 human/porcine xenografts using cyclosporine as immunosuppressant. Some myoblasts developed to become cardiomyocytes. Others transferred their nuclei into host cardiomyocytes through natural cell fusion. As yet others formed skeletal myofibers with satellite cells. De novo production of contractile filaments augmented the heart contractility. Human myoblasts transduced with VEGF165 gene produced six times more capillaries in porcine myocardium than in placebo. Xenograft rejection was not observed for up to 20 weeks despite cyclosporine discontinuation at 6 weeks. Pros and cons of autografts vs. allografts are compared to guide future development of heart cell therapy.
Animals↗
Generation and analysis of mice with a targeted disruption of the arylamine N-acetyltransferase type 2 gene.
Arylamine N-acetyltransferases (NATs) are polymorphic xenobiotic metabolising enzymes, linked to cancer susceptibility in a variety of tissues. In humans and in mice there are multiple NAT isoforms. To identify whether the different isoforms represent inbuilt redundancy or whether they have unique roles, we have generated mice with a null allele of Nat2 by gene targeting. This mouse line conclusively demonstrates that the different isoforms have distinct functions with no compensatory expression in the Nat2 null animals of the other isoforms. In addition, we have used the transgenic line to show the pattern of Nat2 expression during development. Although Nat2 is not essential for embryonic development, it has a widespread tissue distribution from at least embryonic day 9.5. This mouse line now paves the way for the teratological role of Nat2 to be tested.
Amino Acid Transport System A↗
Arylamine N-acetyltransferases: a pharmacogenomic approach to drug metabolism and endogenous function.
The arylamine N-acetyltransferases (NATs) are a unique family of enzymes that catalyse the transfer of an acetyl group from acetyl-CoA to the terminal nitrogen of hydrazine and arylamine drugs and carcinogens. The NATs have been shown to be important in drug detoxification and carcinogen activation, with humans possessing two isoenzymes encoded by polymorphic genes. This polymorphism has pharmacogenetic implications, leading to different rates of inactivation of drugs, including the anti-tubercular agent isoniazid and the anti-hypertensive drug hydralazine. Mice provide a good model for human NAT, allowing genetic manipulation of expression to explore possible endogenous roles of these enzymes. The first three-dimensional NAT structure was resolved for NAT from Salmonella typhimurium, and subsequently the structure of NAT from Mycobacterium smegmatis has been elucidated. These identified a 'Cys-His-Asp' catalytic triad (conserved in all NATs), which is believed to be responsible for the activation of the active site cysteine residue. As more genomic data become available, NAT homologues continue to be found in prokaryotic species, many of which are pathogenic, including Mycobacterium tuberculosis. The discovery of NAT in M. tuberculosis is particularly significant, since this enzyme participates in inactivation of isoniazid in the bacterium, with implications for isoniazid resistance. Structural studies on NAT proteins and phenotypic analyses of organisms (both mice and prokaryotes) following genetic modifications of the nat genes are leading to an understanding of the potentially diverse roles of NAT in endogenous and xenobiotic metabolism. These studies have indicated that NAT, particularly in Mycobacteria, has the potential to be a drug target. Combinatorial chemical approaches, together with in silico structural studies, will allow for advances in the identification of NAT substrates and inhibitors, both as experimental tools and as potential drugs.
Animals↗
Electronic-topological study of structurally diverse cyclooxygenase-2 inhibitors.
A large series of cyclooxygenase-2 (COX-2) inhibitors with diverse skeletons were investigated by means of the Electronic-Topological Method. A system for the COX-2 inhibitor activity prognostication was built with 6 pharmacophores and 6 anti-pharmacophores. The forecasting ability of the system was also tested on different structures, which differ from those that characterize the series studied.
Algorithms↗
Pharmacogenetics of the arylamine N-acetyltransferases.
The arylamine N-acetyltransferases (NATs) are involved in the metabolism of a variety of different compounds that we are exposed to on a daily basis. Many drugs and chemicals found in the environment, such as those in cigarette smoke, car exhaust fumes and in foodstuffs, can be either detoxified by NATs and eliminated from the body or bioactivated to metabolites that have the potential to cause toxicity and/or cancer. NATs have been implicated in some adverse drug reactions and as risk factors for several different types of cancers. As a result, the levels of NATs in the body have important consequences with regard to an individual's susceptibility to certain drug-induced toxicities and cancers. This review focuses on recent advances in the molecular genetics of the human NATs.
Alleles↗
NAT--from bugs to brains. An overview of the 2nd International Workshop on the arylamine N-acetyltransferases.
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Animals↗
Electronic-topological study of the structure-activity relationships in a series of piperidine morphinomimetics.
Structure-activity relationships (SAR) are studied in the series of 4,4-disubstituted piperidine morphinomimetics (42 compounds) by means of the Electronic-Topological Method (ETM). In the frameworks of this approach, its input data were taken as the results of conformational and quantum-mechanical calculations. These calculations had been carried out for all compounds from the series under study, taking into account their neutral and protonated by the nitrogen of piperidine cycle forms. The ETM application resulted in a set of pharmacophores and anti-pharmacophores, which formed a basis of a system used to predict analgesic activity. First of all, the system was tested on known analgesics. Testing has shown a good agreement with the experimental data. Then, the system was applied to a few compounds with similar structures but unknown activity. The results of the study could be used for computer screening and design of novel compounds with analgesics properties as new potential drugs.
Algorithms↗
In vitro genesis of subaxial cervical unilateral facet dislocations through sequential soft tissue ablation.
STUDY DESIGN: In vitro anatomic study investigating the degree of soft tissue disruption required to produce a subaxial cervical unilateral facet dislocation. OBJECTIVES: To develop an understanding of the relative contributions to stability of the subaxial cervical soft tissues and to define an anatomic threshold of injury necessary to produce a unilateral cervical facet dislocation. SUMMARY OF BACKGROUND DATA: The literature at this time is unclear regarding the precise pathomechanics of a cervical unilateral facet dislocation and the required threshold of soft tissue injury necessary for its genesis. Published clinical reports do not make any specific reference to these factors or are unclear in their objectivity. METHODS: Two adjacent vertebra at a time in 10 fresh-frozen subaxial cervical spine specimens (C2-C3 to C6-C7) were transfixed in the coronal plane with 3.5-mm Schanz screws. A steady unilateral vertical distraction force resulting in lateral cervical flexion was applied to these screws as the surrounding cervical soft tissue structures were sequentially ablated. Four experimental models were developed, varying the order of soft tissue disruption. RESULTS: The physiologic coupling of subaxial cervical unilateral distraction and rotation, because of the spatial orientation or inclination of the cervical facet joints, allowed the creation of a unilateral facet dislocation without an additional flexion moment. Disruption of the ipsilateral articular capsule, ligamentum flavum, and more than half of the anulus fibrosus was necessary for the genesis of a unilateral facet dislocation. Disruption of the supraspinous and interspinous ligaments was not necessary but appeared to facilitate or lessen the force required to dislocate a unilateral facet. Disruption of the anterior and posterior longitudinal ligaments and intertransverse ligaments was not necessary to create a unilateral facet dislocation. CONCLUSION: This anatomic study further supports the theory that discontinuity of the anterior and posterior longitudinal ligaments is not necessary for a unilateral facet dislocation to occur. The ipsilateral facet capsule, anulus fibrosus, and ligamentum flavum appear to be the physical soft tissue restraints that need to be disrupted to produce a unilateral facet dislocation.
Adolescent↗
Fenestration of the extracranial vertebral artery: review of the literature.
STUDY DESIGN: A case report on fenestration of the extracranial vertebral artery found at forensic autopsy. OBJECTIVE: To describe an extracranial vertebral artery fenestration involving the subaxial cervical region, assessed radiographically and angiographically at forensic autopsy, in a young man. SUMMARY OF BACKGROUND DATA: Duplications or fenestrations of the extracranial course of the vertebral artery are rare and seen almost exclusively as a coincidental finding in angiographic studies. The terms "fenestration" and "duplication" are often incorrectly used synonymously. The former describes the passage of the duplicated vessel within the vertebral foramen transversarium, whereas the latter refers to the duplicated vessel coursing additionally through the spinal canal. The reported cases describing duplication are more common. Only three cases of vertebral extracranial fenestrations, involving only the upper cervical spinal segments, have been described in the literature. RESULTS: Angiography showed a fenestration of the vertebral artery localized between the intervertebral spaces of C2-C3 and C3-C4. At dissection, the vertebral artery appeared as a single vessel in the area of the fenestration. Histologically, a distinct difference in the thickness and composition of the vessel walls was found between the two vessel trunks. At autopsy, no further anomalies were observed in the vessels supplying the brain, which is contrary to the commonly held belief that fenestration is frequently associated with vascular malformations. CONCLUSION: Fenestration of the extracranial course of the vertebral artery is a developmental or congenital anomaly. A review of the literature demonstrated that this is apparently only a coincidental finding and has no pathologic significance.
Adolescent↗
[Injuries of the thoracic vertebrae in head-first dive into water].
116 patients with cervical spine injuries due to water sport accidents treated in eight Austrian institutions from 1991 to 1998 were reviewed retrospectively. There were 93% male, 72% were 15 to 29 years of age. 93% had injuries from diving into swimming pools or into open water. At discharge 58 patients had Frankel A lesions, 39 had incomplete cord lesions Frankel B to D, and 19 patients had no neurological injury. This data suggest that in Austria approximately one person per one million inhabitants per year sustains a spinal cord injury in a diving accident in shallow water.
Adolescent↗
Arylamine N-acetyltransferases - of mice, men and microorganisms.
Arylamine N-acetyltransferases (NATs) catalyse the transfer of an acetyl group from acetyl CoA to the terminal nitrogen of hydrazine and arylamine drugs and carcinogens. These enzymes are polymorphic and have an important place in the history of pharmacogenetics, being first identified as responsible for the polymorphic inactivation of the anti-tubercular drug isoniazid. NAT has recently been identified within Mycobacterium tuberculosis itself and is an important candidate for modulating the response of mycobacteria to isoniazid. The first three-dimensional structure of the unique NAT family shows the active-site cysteine to be aligned with conserved histidine and aspartate residues to form a catalytic triad, thus providing an activation mechanism for transfer of the acetyl group from acetyl CoA to cysteine. The unique fold could allow different members of the NAT family to play a variety of roles in endogenous and xenobiotic metabolism.
Alleles↗
Arylamine N-acetyltransferase of Mycobacterium tuberculosis is a polymorphic enzyme and a site of isoniazid metabolism.
Arylamine N-acetyltransferases (NATs; E.C 2.3.1.5) N-acetylate arylhydralazine and arylamine substrates using acetyl coenzyme A. Human NAT2 acetylates and inactivates the antituberculosis drug, isoniazid (INH), and is polymorphic. We previously demonstrated that there is a homologue of human NAT2 in Mycobacterium tuberculosis, whose product N-acetylates INH in vitro. We now demonstrate that the nat gene is expressed in M. tuberculosis and M. bovis Bacille Calmette-Guerin (BCG), using reverse transcription-polymerase chain reaction and Western blotting. The NAT protein is active in M. bovis BCG in vivo, as detected by the presence of N-acetyl INH in M. bovis BCG lysates grown in INH. Sequence analysis of the M. tuberculosis nat coding region reveals a single nucleotide polymorphism in 18% of a random cohort of M. tuberculosis clinical isolates, conferring a G to R change. The recombinant mutant protein appears less stable than the wild type, and has an apparent affinity for INH of 10-fold less than the wild type. Modelling the change in M. tuberculosis NAT shows that the G to R change is close to the active site, and supports the experimental findings. Minimum inhibitory concentration data suggest that this polymorphism in nat is linked to low-level changes in the INH susceptibility of M. tuberculosis clinical isolates.
Acetylation↗
Thromboprophylaxis with 60 mg enoxaparin is safe in hip trauma surgery.
BACKGROUND: Little information is available concerning dosage and optimal initiation of thromboprophylactic therapy with low-molecular-weight heparin (enoxaparin) in nonelective hip surgery. The aim of our prospective study was to evaluate the incidence of clinically apparent deep vein thrombosis (DVT), pulmonary embolism (PE), and major hemorrhage in patients receiving thromboprophylaxis with enoxaparin undergoing hip surgery after hip fracture. METHOD: From 946 consecutive patients admitted with hip fractures, 897 were operated on and received enoxaparin according to the following regimen: Preoperative heparinization from time of admission onwards. Administration of 60 mg enoxaparin, in two doses (20 and 40 mg subcutaneously), during the first 5 days postoperatively. Prophylaxis for a minimum of 5 weeks (40 mg daily). RESULTS: Clinical signs of DVT were present in 37 patients (4.2%), who all underwent venography. In five patients, DVT was confirmed (0.6%). None of these patients suffered from PE. Another four patients (0.4%) developed clinical signs of PE, and suspected diagnosis was confirmed by computed tomographic scan in two (0.2%). No deaths because of PE were observed. Major hemorrhage occurred in 42 patients (4.7%), there was one death from hemorrhage caused by an intracerebral event. No case of heparin-induced thrombocytopenia type II was observed. CONCLUSION: Thromboprophylaxis with 60 mg enoxaparin daily, in split doses, starting before surgery, is safe and appropriate in patients with hip fractures. Clinically apparent DVT and PE are rarely observed, and bleeding complications are comparable to those occurring with a conventional thromboprophylactic regimen.
Adult↗
N-Acetyltransferases, sulfotransferases and heterocyclic amine activation in the breast.
Heterocyclic amines are mammary carcinogens in rats and their N-hydroxy metabolites are substrates for subsequent metabolic activation by N-acetyltransferases (NAT) and sulfotransferases (SULT) in man. We investigated the expression of these enzymes in human breast tissue and the relationship between NAT genotype and NAT mRNA expression or enzyme activity. Immunohistochemical staining of sections of breast tissue identified expression of NAT1 and NAT2 protein in human mammary epithelial cells, but not in the stroma. We also measured the formation of DNA adducts of the heterocyclic amines 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in calf thymus DNA after incubation of their promutagenic N-hydroxy metabolites with mammary cytosols prepared from reduction mammoplasty tissue. Experimental observations gained from use of enzyme cofactors and NAT and/or SULT inhibitors on cytosolic enzyme activity, recombinant NAT1 activity and heterocyclic amine-DNA adduct formation suggest that both NAT1 and SULT1A enzymes contribute significantly to the activation of N-hydroxylated heterocyclic amines in mammary tissue. NAT1 mRNA transcript levels were found to be two- to three-fold higher than mRNA transcripts of the NAT2 gene in reduction mammoplasty tissue and mammary epithelial cells. NAT1-specific p-aminobenzoic acid acetylation activity, but not NAT2-specific sulfamethazine acetylation activity, was detectable in mammary cytosols. There was no association apparent between NAT genotype and the levels of NAT mRNA or NAT enzyme activity, or between NAT1 genotype and IQ-DNA adduct formation mediated by mammary cytosols. Western blot analysis of mammary cytosolic protein showed detectable levels of SULT1A1 and SULT1A3.
Amines↗
Evidence towards the role of arylamine N-acetyltransferase in Mycobacterium smegmatis and development of a specific antiserum against the homologous enzyme of Mycobacterium tuberculosis.
Arylamine N-acetyltransferase (NAT) in humans inactivates the anti-tubercular drug isoniazid (INH). Homologues of human NAT are present in Mycobacterium tuberculosis and Mycobacterium smegmatis, where they can acetylate, and hence inactivate, INH. The in vivo role of mycobacterial NAT is not known but heterologous expression of the M. tuberculosis gene increases the INH resistance. The 0.85 kb nat gene is part of a gene cluster in M. smegmatis. The gene is transcribed as a large, 7.5 kb mRNA as demonstrated by Northern analysis. A nat knockout strain of M. smegmatis was generated by targeted disruption. The new strain was confirmed to be devoid of NAT activity. The growth of the knockout strain is considerably delayed compared with the wild-type, due to an extended lag phase. The knockout mutant has an increased sensitivity to INH as would be predicted. The NATs from M. smegmatis and M. tuberculosis have a high degree of homology, except in the region of the C terminus. A specific polyclonal antiserum raised against recombinant NAT protein from M. tuberculosis is described that recognizes a stretch of about twenty residues within the C terminus of M. tuberculosis NAT. This highly specific antiserum will enable comparison of nat expression between isolates of M. tuberculosis.
Acebutolol↗
Genetic aberrations of NAT2 and chromosome 8: their association with progression in transitional cell carcinoma of the urinary bladder.
INTRODUCTION/OBJECTIVE: N-acetyltransferase 2 (NAT2), mapped to 8p22, is a polymorphic enzyme which metabolizes aromatic amines. Loss of heterozygosity of 8p22 is associated with an increased risk of bladder cancer. This study evaluated NAT2 and chromosome 8 in sequential tumours from bladder cancer patients to determine if NAT2 alterations increase the risk of progression. MATERIALS AND METHODS: Thirty-seven sequential carcinomas from 19 patients were assessed using fluorescence in situ hybridization. RESULTS: Five carcinomas showed loss of NAT2; 4 of these were from pTa/pT1 tumours. Polysomy 8 was observed in 4 of 14 (29%) primary carcinomas (pTa/pT1), in 4 of 12 (33%) pTa/pT1 recurrences, and in 90% (9/10) of the detrusor muscle invasive tumours (pT2+). 6 of 8 (75%) locally invasive tumours with polysomy 8 were from patients who subsequently developed disease progression (pT2+). In total, 13.5% (5/37) of the carcinomas were abnormal for NAT2, and 46% (17/37) were abnormal for chromosome 8 copy number. Polysomy 8 was associated with high grade (p = 0.01) and stage (p = 0.03) and disease progression (p = 0.03). CONCLUSION: Whilst there does not appear to be an association between loss of NAT2 and risk of progression in transitional cell carcinoma, the high rate of polysomy of chromosome 8 implies that other genes on this chromosome significantly influence disease progression.
Adult↗