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Paraoxonase (PON1) in Health and Disease

Paraoxonase (PON1) in Health and Disease
Author: Lucio G. Costa
Publisher: Springer Science & Business Media
Total Pages: 226
Release: 2012-12-06
Genre: Science
ISBN: 1461510279

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The paraoxonase or PON family of genes resides on human chromosome 7q2t-22 in the order PONt, PON3 and PON2. PONt was one of the early genes identified as an environmentally relevant gene, in that it is important in determining an individual's sensitivity or resistance to exposure from specific organophosphorus (OP) insecticides. Paraoxonase (PONt) is an A esterase (i. e. , not inhibited by OP compounds) initially identified for its ability to catalytically hydrolyze paraoxon, the toxic metabolite (oxon form) of the insecticide parathion. Evidence accumulated in the past several years has established that this enzyme, which is present at variable levels in liver and serum of different individuals, is an important determinant of sensitivity to toxicity of specific organophosphorus compounds including chlorpyrifos oxon and diazoxon. Recent experiments have pointed out that it is the catalytic efficiency of PONt together with the levels of PONt that are important in determining the degree of resistance. Surprisingly, even though PONt has a higher catalytic efficiency than PONtQ)92 for paraoxon RJ92 hydrolysis, it does not provide significant in vivo protection against an exposure to paraoxon. Interest in this enzyme has also emerged from the finding that it displays genetic polymorphisms in most populations, with a significant number of the individuals in a given population canying a PONt gene that puts them at risk for a specific OP exposure.


The Paraoxonases: Their Role in Disease Development and Xenobiotic Metabolism

The Paraoxonases: Their Role in Disease Development and Xenobiotic Metabolism
Author: Bharti Mackness
Publisher: Springer Science & Business Media
Total Pages: 322
Release: 2007-10-26
Genre: Medical
ISBN: 1402065612

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In September 2006 the 2nd International Conference on Paraoxonases took place in Hajdúszoboszló, Hungary, bringing together the world's foremost experts in the field. The current book is a distillation of the plenary lectures which took place at the meeting, resulting in a comprehensive up-to-date, state-of-the-art review of current paraoxonase research. The book details a unique and novel enzyme whose physiological/pathological function(s) are just starting to be revealed.


An Enzyme Immunoassay for Human Serum Paraoxonase 1 (PON 1)

An Enzyme Immunoassay for Human Serum Paraoxonase 1 (PON 1)
Author:
Publisher:
Total Pages: 149
Release: 2007
Genre:
ISBN:

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Human Serum Paraoxonase 1 (PON 1) plays a dual physiological role. Low PON status levels are an emerging risk factor for coronary vascular disease (CVD) where it is has been to shown to be responsible for HDL's (high-density lipoproteins) ability to protect LDL (low-density lipoproteins) from oxidative modification. PON is also a critical player in the metabolism of organophosphate insecticides and other environmental intoxicants. The analysis of PON1 requires the measurement of three factors, which directly and significantly impact the role of this enzyme in humans: (1) polymorphism classification, (2) enzymatic activity, and (3) enzyme concentration. The combination of these three factors referred is referred to as 'PON 1 Status'. Determination of an individual's PON 1 status is necessary to accurately classify an individual in terms of relative risk for CVD as well as susceptibility to environmental poisoning. Previous work has produced ways to measure PON 1 activity and determine molecular polymorphisms. To date, no commercial assay has been developed to measure PON 1 concentration. There is consequently a need to develop a PON 1 Enzyme Linked Immunosorbant Assay (ELISA) to facilitate the quantification of the enzyme in human serum. The development of a functional ELISA will enable researchers to determine overall PON 1 status of individuals, measuring concentration in addition to genotype. The specific aims of this project are to: (1) Culture, purify and characterize a previously developed mouse-anti human PON 1 monoclonal antibody. (2) Prepare human PON 1 protein standard by isolation and purification assays from large units of human plasma. (3) Generate, purify and characterize a polyclonal goat anti-human antibody. (4) Design a PON 1 ELISA using the standards, monoclonal antibody and polyclonal antibody to produce a functional, sensitive and rapid assay to measure human serum PON 1. The results of this research will provide the necessary PON 1 concentration assay to complement the phenotype and activity assays already established. These 3 assays will provide the comprehensive analytical tools necessary to more thoroughly investigate the role of PON1 in human health and disease states.


Paraoxonases in Inflammation, Infection, and Toxicology

Paraoxonases in Inflammation, Infection, and Toxicology
Author: Srinivasa T. Reddy
Publisher: Humana Press
Total Pages: 212
Release: 2012-02-25
Genre: Science
ISBN: 9781617796753

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Biomarkers are used in many aspects of health surveillance to identify disease pr- ence, track disease progression, monitor drug delivery or metabolism, or monitor chemical exposure. There is a recognized need to expand and improve biomarker identi'cation and quanti'cation. Exposures to the xenobiotic organophosphates (OPs) range from low-level, chronic exposure during pesticide application (e. g. , on farms, in residences, or in the workplace) to high-dose, acute exposures incl- ing release of nerve agents or toxic industrial OPs. OPs can have both rapid and chronic toxicity, due to their action on speci'c esterases and lipases, most notably acetylcholinesterase (AChE) and neuropathic target esterase (NTE). In each of the above examples, a rapid and accurate assessment of the OP to which the person was exposed, degree of exposure, and time period of exposure will help direct therapy to the victim and assess the level of threat to others. Traditionally, metabolites for speci'c OPs can be measured in the urine after an exposure, such as 3,5,6-trichloro- 2-pyridinol for chlorpyrifos (CPS). However, there are several problems with this method. Usually, the metabolite is excreted for only a short period of several days after a signi'cant exposure. In addition, due to the widespread use of CPS and en- ronmental persistence of its breakdown products, the metabolites appear at a high background level in the general population (Hill et al. 1995). Their appearance does not indicate whether the individual was exposed to the harmful parent compound, or the harmless breakdown product.


Applications of Toxicogenomic Technologies to Predictive Toxicology and Risk Assessment

Applications of Toxicogenomic Technologies to Predictive Toxicology and Risk Assessment
Author: National Research Council
Publisher: National Academies Press
Total Pages: 300
Release: 2007-12-19
Genre: Science
ISBN: 0309112982

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The new field of toxicogenomics presents a potentially powerful set of tools to better understand the health effects of exposures to toxicants in the environment. At the request of the National Institute of Environmental Health Sciences, the National Research Council assembled a committee to identify the benefits of toxicogenomics, the challenges to achieving them, and potential approaches to overcoming such challenges. The report concludes that realizing the potential of toxicogenomics to improve public health decisions will require a concerted effort to generate data, make use of existing data, and study data in new waysâ€"an effort requiring funding, interagency coordination, and data management strategies.


High Density Lipoproteins

High Density Lipoproteins
Author: Arnold von Eckardstein
Publisher: Springer
Total Pages: 0
Release: 2015-01-13
Genre: Medical
ISBN: 9783319096643

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In this Handbook of Experimental Pharmacology on “High Density Lipoproteins – from biological understanding to clinical exploitation” contributing authors (members of COST Action BM0904/HDLnet) summarize in more than 20 chapters our current knowledge on the structure, function, metabolism and regulation of HDL in health and several diseases as well as the status of past and ongoing attempts of therapeutic exploitation. The book is of interest to researchers in academia and industry focusing on lipoprotein metabolism, cardiovascular diseases and immunology as well as clinical pharmacologists, cardiologists, diabetologists, nephrologists and other clinicians interested in metabolic or inflammatory diseases.


Paraxonase-1 Variants Alter Stability and Activity

Paraxonase-1 Variants Alter Stability and Activity
Author: Stephanie M. Suzuki
Publisher:
Total Pages: 153
Release: 2014
Genre:
ISBN:

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Paraoxonase-1 (PON1) is a high-density lipoprotein-associated enzyme that has been extensively studied due to its ability to hydrolyze and inactivate toxic compounds such as organophosphate (OP) pesticide metabolites and its anti-atherogenic properties. However, the physiological substrate of PON1 is still unknown. Protein therapeutics have been proposed as a treatment for OP intoxication and PON1 is a major candidate. Production in bacterial cells would allow for expression of an unglycosylated enzyme which would reduce the possibility of an immunogenic response. It would also allow for easy mutagenesis of PON1 and scale-up production. We developed a system for expression of recombinant untagged native and variant human PON1s (rHuPON1s) in E. coli cells. The proteins were purified using multiple column chromatographic steps. This was the first expression, purification, and characterization of active native human PON1 from bacterial cells. A variant PON1, rHuPON1K192, had increased catalytic efficiency of hydrolysis for the OPs diazoxon (DZO), chlorpyrifos oxon, and paraoxon. Catalytic efficiency is an important characteristic as previous experiments demonstrated that it determines whether PON1 will protect against a specific OP in vivo. The rHuPON1K192 variant was injected in PON1 knockout (PON1-/-) mice and was found to be long-lasting in plasma, nontoxic, and protect against a 1 LD50 dose of dermal DZO and prevent the lethality of high doses (2-3 LD50) of DZO. Other rHuPON1 variants were also expressed, purified, and characterized. Some variants with a single amino acid change had increased protein stability and calcium binding. On the other hand, the disease-associated variant rHuPON1V109I had decreased protein stability. While PON1's physiological substrate is still unclear, homocysteine thiolactone (HCTL), a toxic, reactive metabolite of the amino acid homologue homocysteine, has been proposed as the physiological substrate of PON1. Bleomycin hydrolase (Blmh), another enzyme, was described as the HCTLase in tissues. We purified another HCTLase from liver and identified it by MS as biphenyl hydrolase-like protein (BPHL). Recombinant BPHL (rBPHL) was cloned, expressed, and characterized. BPHL's high catalytic efficiency for HCTL, which is 7700 times greater than that of PON1, total HCTLase activity calculations, and liver HCTLase inhibition assays suggest that BPHL is the most physiologically-relevant HCTLase isolated to date.


Toxicology of Organophosphate and Carbamate Compounds

Toxicology of Organophosphate and Carbamate Compounds
Author: Ramesh C Gupta
Publisher: Academic Press
Total Pages: 781
Release: 2011-04-28
Genre: Technology & Engineering
ISBN: 0080543103

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This text/reference book provides the most comprehensive coverage of anticholinesterase compounds (Organophosphates and Carbamates), which constitute the largest number of chemicals that are primarily used as insecticides in agriculture, industry, and around the home/garden. Some OPs (nerve agents) have been used in chemical warfare and terrorist attacks, while some OPs and CMs have been recommended as therapeutic agents in human medicine as well as in veterinary medicine. Many chemicals of both classes are extremely toxic and lack selectivity, thus their inadvertent/accidental use continues to pose a threat to human and animal health, aquatic systems and wildlife. These anticholinesterase agents produce a variety of toxicological effects in target and nontarget organs. In light of this complexicity, this multi-authored book is written by the well known scientists from many countries. The book is organized into nine sections, with a total of 49 chapters, to provide in-depth knowledge on various aspects of OP and CM compounds, including their use, classification, mechanism-based toxicity, and prophylactic and therapeutic measurements. Several chapters are written with special emphasis to cover timely topics, such as chemical warfare agents, physiologically-based pharmacokinetic modeling, structure and function of cholinesterases, paraoxonase, carboxylesterases; developmental neurotoxicity, the intermediate syndrome, oxidative stress, endocrine disruption, and DNA damage/gene expression and carcinogenesis. Section-VI with 5 chapters is specifically devoted to risk assessment, and safety and regulatory guidelines for pesticides. Describes everything you need to know about Organophosphates and Carbamates Extensively covers pesticides, nerve agents, therapeutic drugs, and flame retardants Describes epidemiology of the world's major disasters involving Organophosphates and Carbamates Covers animal, human, aquatic, and wildlife toxicity of Anticholinesterases Insights into in-depth cholinergic and noncholinergic mechanisms of toxicity Describes recent advancements in cholinesterases, paraoxonases, carboxylesterases, oxidative stress, endocrine disruption, cardiac and pulmonary toxicity, and carcinogenesis Provides in vitro and in vivo models for neurotoxicity testing Integrates knowledge of studies in lab animals and humans Offers risk/safety assessment and national/international guidelines for permissible levels of pesticide residues Describes management of Anticholinesterase poisoning in humans


Oxidative Stress and Vascular Disease

Oxidative Stress and Vascular Disease
Author: John F. Keaney Jr.
Publisher: Springer Science & Business Media
Total Pages: 404
Release: 1999-12-31
Genre: Medical
ISBN: 9780792386780

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One of the major biomedical triumphs of the post-World War II era was the defmitive demonstration that hypercholesterolemia is a key causative factor in atherosclerosis; that hypercholesterolemia can be effectively treated; and that treatment significantly reduces not only coronary disease mortality but also all cause mortality. Treatment to lower plasma levels of cholesterol - primarily low density lipoprotein (LDL) cholesterol - is now accepted as best medical practice and both physicians and patients are being educated to take aggressive measures to lower LDL. We can confidently look forward to important decreases in the toll of coronary artery disease over the coming decades. However, there is still uncertainty as to the exact mechanisms by which elevated plasma cholesterol and LDL levels initiate and favor the progression of lesions. There is general consensus that one of the earliest responses to hypercholesterolemia is the adhesion of monocytes to aortic endothelial cells followed by their penetration into the subendothelial space, where they differentiate into macrophages. These cells, and also medial smooth muscle cells that have migrated into the subendothelial space, then become loaded with mUltiple, large droplets of cholesterol esters . . . the hallmark of the earliest visible atherosclerotic lesion, the so-called fatty streak. This lesion is the precursor of the more advanced lesions, both in animal models and in humans. Thus the centrality of hypercholesterolemia cannot be overstated. Still, the atherogenic process is complex and evolves over a long period of time.