Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.1.8 (cholinesterase)
12,691 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Many organophosphorus compounds (OPs) are potent cholinesterase inhibitors, accounting for their use as insecticides and, unfortunately, also as nerve agents. Each year there are approximately 3 million pesticide poisonings world-wide resulting in 220,00 deaths. In 1990, there were 1.36 million kg of chlorpyrifos, 4.67 million kg of diazinon and 1.23 million kg of ethyl parathion manufactured in the USA (data supplied by the USEPA). In addition to exposure risks during pesticide manufacturing, distribution and use, there are risks associated with the major international effort aimed at destroying the arsenals of nerve agents, including soman and sarin. The United States has pledged to destroy approximately 25,000 tons of chemical agents by the end of the decade. The high density lipoprotein (HDL)-associated enzyme paraoxonase (PON1) contributes significantly to the detoxication of several OPs (Fig. 1). The insecticides parathion, chlorpyrifos and diazinon are bioactivated to potent cholinesterase inhibitors by cytochrome P-450 systems. The resulting toxic oxon forms can be hydrolysed by PON1, which also hydrolyses the nerve agents soman and sarin (Fig. 1). PON1 is polymorphic in human populations and different individuals also express widely different levels of this enzyme. The Arg192 (R192) PON1 isoform hydrolyses paraoxon rapidly, while the Gln192 (Q191) isoform hydrolyses paraoxon slowly. Both isoforms hydrolyse chlorpyrifos-oxon and phenylacetate at approximately the same rate. The role of PON1 in OP detoxication is physiologically significant. Injected PON1 protects against OP poisoning in rodent model systems and interspecies differences in PON1 activity correlate well with observed median lethal dose (LD50) values. We report here a simple enzyme analysis that provides a clear resolution of PON1 genotypes and phenotypes allowing for a reasonable assessment of an individual's probable susceptibility or resistance to a given OP, extending earlier studies on this system. We also show that the effect of the PON1 polymorphism is reversed for the hydrolysis of diazoxon, soman and especially sarin, thus changing the view of which PON1 isoform is considered to be protective.
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PMID:The effect of the human serum paraoxonase polymorphism is reversed with diazoxon, soman and sarin. 889 66

Different kinds of organophosphorous compounds (OP) are used as pesticides in Turkish agriculture. Suicidal, accidental, or occupational exposure may occur in developing countries. OP inhibit acetylcholinesterase (AChE) activities; on the other hand, serum paraoxonase (PON1) hydrolyzes the toxic metabolites of a variety of OP. In recent years, some studies have shown that PON1 activity is an important marker in individuals who are exposed to OP. Both serum cholinesterase and PON1 activities were measured spectrophotometrically from 18 male agricultural workers who were chronically exposed to azinphos methyl, chlorpyriphos, or malathion and other pesticides during cereal spraying, transportation, and storage. The individuals were classified according to PON1 phenotypes using the antimode 60% stimulation method to determine the dividing point between non-salt-stimulated, A type (homozygotes for the low-activity allele), and salt-stimulated AB (heterozygotes) and B types (homozygotes for the high-activity allele). A positive correlation was found between AChE activities and percent of PON1 stimulation. The individuals with phenotype A had the lowest enzyme activities. This study suggests that individuals with phenotype A might be more sensitive to OP-induced toxicity.
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PMID:Paraoxonase and acetylcholinesterase activities in humans exposed to organophosphorous compounds. 1063 39

Susceptibility to organophosphorus (OP) insecticides and nerve agents is strongly influenced by genetic and developmental factors. A number of organophosphorothioate insecticides are detoxified in part via a two-step pathway involving bioactivation of the parent compound by the cytochrome P450 systems, then hydrolysis of the resulting oxygenated metabolite (oxon) by serum and liver paraoxonases (PON1). Serum PON1 has been shown to be polymorphic in human populations. The Arg192 isoform (PON1R192) of this HDL-associated protein hydrolyzes paraoxon (POX) at a high rate, while the Gln192 isoform (PON1Q192) hydrolyzes paraoxon at a low rate. The effect of the polymorphism is reversed for the hydrolysis of diazoxon (DZO), soman and particularly sarin. Phenylacetate is hydrolyzed at approximately the same rate by both PON1 isoforms and chlorpyrifos oxon (CPO) slightly faster by the PON1R192 isoform. In addition to the effect of the amino acid substitution on rates of toxicant hydrolysis, two other factors influence these rates. The expression of PON1 is developmentally regulated. Newborns have very low levels of PON1. Adult levels in rats and mice are reached at 3 weeks of age and in humans, sometime after 6 months of age. In addition, among individuals of a given genotype, there is at least a 13-fold difference in expression of PON1 that is stable over time. Dose/response experiments with normal mice injected with purified PON1 and with PON1 knockout mice have clearly demonstrated that the observed differences of in vitro rates of hydrolysis are significant in determining differential sensitivities to specific insecticides processed through the P450/PON1 pathway. Injection of purified rabbit PON1 protects mice from cholinesterase inhibition by chlorpyrifos (CPS) and CPO. Knockout mice are much more sensitive to CPO and DZO than are their PON1+/+ littermates or wild-type mice. A number of recent reports have also indicated that the PON1R192 isoform may be a risk factor for cardiovascular disease. Studies with PON1 knockout mice are also consistent with a role of PON1 in preventing vascular disease.
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PMID:Genetic and temporal determinants of pesticide sensitivity: role of paraoxonase (PON1). 1079 89

The potential of obidoxime and other pyridinium-4-aldoximes to reactivate dimethyl- and diethylphosphorylated cholinesterases is markedly restricted by the inevitable formation of rather stable phosphoryl oximes (POXs) with high anticholinesterase activity. This effect is hardly seen with very dilute enzyme preparations, but becomes significant at physiological enzyme concentrations. Human plasma with the butyrylcholinesterase irreversibly blocked by soman was able to stimulate obidoxime-induced reactivation of concentrated erythrocyte acetylcholinesterase (Ery-AChE) to the same extent as was observed with a dilute preparation, suggesting phosphoryl oxime-destroying capacity. The inactivating factor, which was tentatively termed POX-hydrolase, had (1) a molecular weight of >100 kDa; (2) required Ca2+ , which could not be substituted by Zn2+ or Mg2+; and (3) lost its catalytic activity reversibly in the presence of ethylenediamine-tetraacetic acid (EDTA). The enzyme activity varied widely (20-fold) among different subjects and did not follow the activity pattern of human serum paraoxonase (PON1). Rabbit plasma with its particularly high paraoxonase content showed only weak POX-hydrolase activity. These data suggest POX-hydrolase to be a different entity. POX-hydrolase was most active with the putative phosphoryl-obidoxime from paraoxon-ethyl, less with the product from paraoxon-methyl and least with that from diisopropylfluorophosphate. The analogue TMB-4 reacted similarly to obidoxime. The putative phosphonyl oximes arising by the reaction of obidoxime with nerve agents were apparently not cleaved. The variation in POX-hydrolase activity may additionally contribute to the variable response to oxime therapy in patients with organophosphate insecticide poisoning.
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PMID:The phosphoryl oxime-destroying activity of human plasma. 1081 64

Human paraoxonase (PON1) is a polymorphic, high-density lipoprotein (HDL)-associated esterase that hydrolyzes the toxic metabolites of several organophosphorus (OP) insecticides and nerve agents. The activity polymorphism is determined by a Gln/Arg (Q/R) substitution at position 192. Injection of purified PON1 protects animals from OP poisoning. In the present study, we investigated the in-vivo function of PON1 for detoxifying organophosphorus insecticides in PON1-knockout mice that were challenged via dermal exposure with diazoxon, diazinon and paraoxon. PON1-knockout mice were extremely sensitive to diazoxon. Doses (2 and 4 mg/kg) that caused no cholinesterase (ChE) inhibition in wild-type mice were lethal to the knockout mice, which also showed slightly increased sensitivity to the parent compound diazinon. Surprisingly, these knockout mice did not show increased sensitivity to paraoxon. In-vitro assays indicated that the PON1R192 isoform hydrolyzed diazoxon less rapidly than did the PON1Q192 isoform. In-vivo analysis, where PON1-knockout mice received the same amount of either PON1(192) isoform via intraperitoneal (i.p.) injection 4 h prior to exposure, showed that both isoforms provided a similar degree of protection against diazoxon, while PON1R192 conferred better protection against chlorpyrifos-oxon than PON1Q192. Injection of purified rabbit PON1 or either human PON1(192) isoform did not protect PONI-knockout mice from paraoxon toxicity, nor did over-expression of the human PON1R192 transgene in wild-type mice. Kinetic analysis of the two human PON1(192) isoforms revealed that the catalytic efficiency (Vmax/Km) determines the in-vivo efficacy of PON1 for organophosphorus detoxication. The results indicate that PON1 plays a major role in the detoxication of diazoxon and chlorpyrifos oxon but not paraoxon.
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PMID:Catalytic efficiency determines the in-vivo efficacy of PON1 for detoxifying organophosphorus compounds. 1119 81

In a recent study on Gulf War veterans who developed delayed neurotoxicity symptoms, we found their levels of serum paraoxonase (PON1) isozyme type Q to be significantly lower than in the control, unaffected veteran group. These results were obtained in 25 ill veterans and 20 well control subjects, of which 10 were deployed and 10 were nondeployed battalion members who remained in the United States during the Gulf War. The blood samples were also assayed for serum butyrylcholinesterase in our laboratory, and more recently in Dr. C. Broomfield's laboratory for somanase and sarinase activities. The cholinesterase activities showed no significant correlation with the PON1 isozyme levels or the severity of the clinical symptoms, but the somanase and sarinase levels ran parallel to the PON1 type Q isozyme concentrations. Although there is no direct evidence that these Gulf War veterans were directly exposed to or encountered either of these nerve gases, they may have been exposed to some environmental or chemical toxin with a similar preference for hydrolysis by the PON1 type Q isozyme. The number of subjects is relatively small, but the results should encourage other investigators to examine both the individual phenotypes and the levels of PON1 isozymes in other groups exhibiting neurological symptoms.
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PMID:Serum paraoxonase (PON1) isozymes: the quantitative analysis of isozymes affecting individual sensitivity to environmental chemicals. 1125 53

Ideally we would like to treat people exposed to nerve agents with an enzyme that rapidly destroys nerve agents. The enzymes considered for such a role include human butyrylcholinesterase (BChE), acetylcholinesterase (AChE), carboxylesterase and paraoxonase (PON1). Success has been achieved in endowing BChE with the ability to hydrolyze organophosphates. The G117H mutant of BCHE hydrolyzes sarin and VX, whereas the double mutant G117H/E197Q hydrolyzes soman (Millard et al. Biochemistry 1995; 34: 15925-15933; 1998; 37: 237-247). However, the rates of organophosphate hydrolysis are slow and a faster organophosphate hydrolase is being sought. Native PON1 hydrolyzes paraoxon with a catalytic efficiency, of 2.4 x 10(6) M(-1) x min(-1), and our goal is to improve the organophosphate hydrolase activity of PON1. To achieve this we need to identify the amino acids in the active site of PON1. Using site-directed mutagenesis and expression in human 293T cells, we have identified the following eight amino acids as being essential to PON1 activity: W280, H114, H133, H154, H242, H284, E52 and D53. Fluorescence of PON1 complexed to terbium ion shows that at least one tryptophan is close to the calcium binding site.
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PMID:The active site of human paraoxonase (PON1). 1192 Sep 13

Human serum paraoxonase (PON1) and perhaps other mammalian paraoxonases catalyzes the hydrolysis of certain organophosphorus (OP) insecticides and nerve gases and so may alter significantly an individual's susceptibility to the toxicity of these chemicals. Serum PON1 exhibits a substrate dependent polymorphism and this polymorphism shows great interethnic variability. This study focused on the investigation of PON1, arylesterase and cholinesterase activities in 28 acute OP insecticide poisoning cases. Insecticide analysis were performed by GC-NPD and activities of enzymes were measured by using spectrophotometer. The activity levels for salt stimulated PON1, basal PON1 and arylesterase were found as 78.83 (35.39-186.13), 39.97 (2.49-80.43) micromol/min/l and 126.26 (36.34-288.24) mmol/min/l respectively. On the other hand the activity levels for butyrylcholinesterase (BTC) and acetylcholinesterase (AchE) were found as 797.23 (106.3-3823)U/l and 4.65 (0.21-30.29)U/ml. There was a correlation between percent stimulation of PON1 and BTC activities (r=0.446, P<0.05), but this correlation was lower than in cases who exposed to OP insecticides chronically. As a conclusion, in chronic and acute OP exposure, both PON1 level and phenotype must be taken into consideration.
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PMID:Human serum paraoxonase (PON1) activity in acute organophosphorous insecticide poisoning. 1274 1

Organophosphorus (OP) compounds are still among the most widely used insecticides, and their main mechanism of acute toxicity is associated with inhibition of acetylcholinesterase. Measurements of urine metabolites and of blood cholinesterase activity are established biomarkers of exposure to OPs and of early biological effects. In recent years, increasing attention has been given to biomarkers of susceptibility to OP toxicity. Here we discuss the polymorphisms of paraoxonase (PON1), a liver and serum enzyme that hydrolyzes a number of OP compounds, and its role in modulating the toxicity of OPs. We stress the importance of determining PON1 status, which encompasses the PON1192Q/R polymorphism (that affects catalytic ability toward different substrates) and PON1 levels (which are modulated in part by a C-108T polymorphism) over straight genotyping. Epidemiological studies on OP-exposed workers that include assessment of PON1 status to validate in human populations the role of PON1 as a determinant of susceptibility to OPs, as indicated by animal studies, are needed. Documentation of exposure and of early health effects would be most relevant to increase the predictive value of the test.
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PMID:Measurement of paraoxonase (PON1) status as a potential biomarker of susceptibility to organophosphate toxicity. 1565 99

Changes in erythrocyte delta-aminolevulinic acid dehydratase (ALA-D) have been reported after exposure to different pesticides, including organophosphates and paraquat. In this study, we have determined ALA-D in 135 pesticide applicators (sprayers) from an intensive agriculture setting at two periods with different pesticide exposure. Acetylcholinesterase (AChE) was used as a reference biomarker. The effects of the combined polymorphism of enzymes involved in the detoxification of pesticides (paraoxonase (PON1), benzoylcholinesterase (BChE), and glutathione S-transferase (GSTM1 and GSTT1)) on the level of the target erythrocyte enzymes were also studied as biomarkers of individual susceptibility. Sprayers presented significant lower levels of ALA-D and AChE than controls (41.3% and 14.5%, respectively) at the high exposure period. When all biomarkers of individual susceptibility to pesticides were considered at the same time, the GSTT1 null allele determined higher ALA-D and AChE activities at the period of high exposure to pesticides. PON1 R allele in turn determined lower AChE activity at the low exposure period. Null genotype for both GST subclasses (GSTM1 and GSTT1) was found to be the unique independent predictor of pesticide-related symptomatology. Interestingly, sprayers were consistently underrepresented among carriers of "unfavourable" BChE variants. In conclusion, ALA-D appears to be an important biological indicator of pesticide exposure and PON1 and GSTT1 are relevant determinants of susceptibility to chronic pesticide poisoning.
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PMID:Changes in erythrocyte enzymes in humans long-term exposed to pesticides: influence of several markers of individual susceptibility. 1592 24


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