Polymorphisms of Paraoxonase (PON1) and Their Significance in Clinical Toxicology of Organophosphates

Costa, Lucio G.; Cole, Toby B.; Furlong, Clement E.

doi:10.1081/clt-120018269

Cited by 91 publications

(58 citation statements)

References 41 publications

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“…It is believed that metabolism rates of various OP compounds influence susceptibility to OP toxicity, and that individual differences in xenobiotic metabolism may modify the adverse effects from OP exposure (Hernandez et al, 1999;Costa et al, 2003Costa et al, , 2005. A number of OP compounds are metabolized in part through bioactivation of the parent compound by the cytochrome P450 systems, followed by hydrolysis of the resulting aryl ester (oxon) by paraoxonases (Furlong et al, 2000b).…”

Section: Introductionmentioning

confidence: 99%

Paraoxonase status and plasma butyrylcholinesterase activity in chlorpyrifos manufacturing workers

Albers

Garabrant

Berent

et al. 2009

J Expo Sci Environ Epidemiol

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Chlorpyrifos is an organophosphorus (OP) anticholinesterase insecticide. Paraoxonase (PON1) is an enzyme found in liver and plasma that hydrolyzes a number of OP compounds. PON1 polymorphisms include a glutamine (Q)/arginine (R) substitution at position 192 (PON1 Q192R ) that affects hydrolysis of OP substrates, with the PON1 192Q allotype hydrolyzing chlorpyrifos oxon less efficiently than the PON1 192R allotype, a variation potentially important in determining susceptibility to chlorpyrifos. We studied 53 chlorpyrifos workers and 60 referents during 1 year and estimated chlorpyrifos exposure using industrial hygiene and employment records and excretion of the chlorpyrifos metabolite 3,5,6-trichloro-2-pyridinol (TCP). Plasma butyrylcholinesterase (BuChE) activity, which may by inhibited by chlorpyrifos exposure, was measured monthly. In addition, plasma samples were assayed for paraoxonase (PONase), diazoxonase (DZOase), and chlorpyrifosoxonase (CPOase) activity to determine PON1 status (inferred genotypes and their functional activity). Linear regression analyses modeled BuChE activity as a function of chlorpyrifos exposure and covariates. We postulated that the level of CPOase activity and the inferred PON1 192 genotype (together reflecting PON1 status) would differ between groups and that PON1 status would modify the models of chlorpyrifos exposure on BuChE activity. Chlorpyrifos workers and referents had a 100-fold difference in cumulative chlorpyrifos exposure. Contrary to our hypotheses, mean CPOase activity was similar in both groups (P ¼ 0.58) and PON1 192Q showed a slight overrepresentation, not an underrepresentation, in the chlorpyrifos group compared with referents (PON1 192QQ , 51% chlorpyrifos, 40% referent; PON 192QR , 43% chlorpyrifos, 40% referent; PON 192RR , 6% chlorpyrifos, 20% referent, P ¼ 0.08). In our models, BuChE activity was significantly inversely associated with measures of interim chlorpyrifos exposure, but the biological effects of chlorpyrifos exposure on BuChE activity were not modified by PON1 inferred genotype or CPOase activity.

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Section: Introductionmentioning

confidence: 99%

Paraoxonase status and plasma butyrylcholinesterase activity in chlorpyrifos manufacturing workers

Albers

Garabrant

Berent

et al. 2009

J Expo Sci Environ Epidemiol

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“…Thus, people with the Q allozyme (genotype QQ or QR) are expected to have greater hydrolysis of sarin than people homozygous for the R allele (genotype RR). Animal studies support the role of PON1 in protection against the toxicity of some OP compounds (Costa et al 2003). The prevalence of the R allele is about 0.3 in Caucasian populations but 0.66 in the Japanese population (Yamasaki et al 1997).…”

Section: Iom Committee Conclusion On Gulf War Health Risk Factorsmentioning

confidence: 99%

Toxicological assessments of Gulf War veterans

Brown

2006

Phil. Trans. R. Soc. B

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Concerns about unexplained illnesses among veterans of the 1991 Gulf War appeared soon after that conflict ended. Many environmental causes have been suggested, including possible exposure to depleted uranium munitions, vaccines and other drugs used to protect troops, deliberate or accidental exposure to chemical warfare agents and pesticides and smoke from oil-well fires. To help resolve these issues, US and UK governments have sought independent expert scientific advice from prestigious, independent scientific and public health experts, including the US National Academies of Science and the UK Royal Society and Medical Research Council. Their authoritative and independent scientific and medical reviews shed light on a wide range of Gulf War environmental hazards. However, they have added little to our understanding of Gulf War veterans' illnesses, because identified health effects have been previously well characterized, primarily in the occupational health literature. This effort has not identified any new health effects or unique syndromes associated with the evaluated environmental hazards. Nor do their findings provide an explanation for significant amounts of illnesses among veterans of the 1991 Gulf War. Nevertheless, these independent and highly credible scientific reviews have proven to be an effective means for evaluating potential health effects from deployment-related environmental hazards.

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“…Two genes are known to increase susceptibility to organophosphate pesticides: acetylcholinesterase and paraoxonase. About 4% of the population carries a gene that results in lower levels of acetylcholinesterase, the target enzyme of organophosphates (which, in turn, increases the vulnerability of the developing brain to organophosphate pesticides; Costa et al, 2003). Another family of genetically determined enzymes, paraoxonase, further modifies an individual's susceptibility to organophosphate pesticide toxicity.…”

Section: Intrinsic Factorsmentioning

confidence: 99%

Expressing urine from a gel disposable diaper for biomonitoring using phthalates as an example

Liu

Xia

Guo

et al. 2012

J Expo Sci Environ Epidemiol

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The urinary metabolites of phthalates are well-accepted exposure biomarkers for adults and children older than 6 years but are not commonly used for infants owing to non-convenient sampling. In the light of this situation, a novel sampling method based on monitoring the urine expressed from the gel diaper was developed. The urine was expressed from the gel absorbent after mixing the absorbent with CaCl2 and then collected by a laboratory-made device; the urinary phthalate metabolites were extracted and cleaned using a solid-phase extraction (SPE) column and analyzed with high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry / mass spectrometry. To evaluate the method's feasibility, the following factors were investigated: the proportion of CaCl2 to gel absorbent, the urination volume variation and the target compounds' deposition bias in the diaper, the matrix blank of the different diaper brands, the storage stabilities and the recoveries of creatinine and phthalate metabolites in the expressed urine. Mono-methyl phthalate, mono-ethyl phthalate, mono-butyl phthalate, mono-benzyl phthalate, mono-2-ethylhexyl phthalate and mono-2-ethyl-5-oxohexyl phthalate were involved. 70-80% of the urine can be expressed from the diaper, and the expressed spiking recoveries and the limit of detection of mono-phthalates ranged from 88.5-115% and 0.21-0.50 ng/ml. The method was applied to measure phthalate metabolites in 65 gel diaper samples from 15 infants, and the pilot data suggests the infants are commonly exposed to phthalates. In summary, the method for monitoring of infant exposure to phthalates is sound and validated, and the potential health effects from the vulnerable infants' exposure to phthalates should be concerned.39th Scientific Research Foundation for the Returned Overseas Chinese Scholars (SRF for ROCS); Hundred Talent Program of Chinese Academy of Sciences (CAS); CAS/SAFEA International Partnership Program for Creative Research Teams [KZCX2-YW-T08

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Polymorphisms of Paraoxonase (PON1) and Their Significance in Clinical Toxicology of Organophosphates

Cited by 91 publications

References 41 publications

Paraoxonase status and plasma butyrylcholinesterase activity in chlorpyrifos manufacturing workers

Paraoxonase status and plasma butyrylcholinesterase activity in chlorpyrifos manufacturing workers

Toxicological assessments of Gulf War veterans

Expressing urine from a gel disposable diaper for biomonitoring using phthalates as an example

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