Expression of human paraoxonase (PON1) during development

Cole, Toby B.; Jampsa, Rachel L.; Walter, Betsy J.; Arndt, T; Richter, Rebecca J.; Shih, Diana M.; Tward, Aaron D.; Lusis, Aldons J.; Jack, Rhona M.; Costa, Lucio G.; Furlong, Clement E.

doi:10.1097/00008571-200306000-00007

Cited by 100 publications

(88 citation statements)

References 45 publications

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“…3). A transgenic mouse strain that lacks endogenous Pon1 but has the human PON1 gene exhibited a similar developmental pattern of expression as wild-type mice, indicating conserved developmental regulatory elements between mouse and human PON1 (Cole et al, 2003), making our data helpful for mechanistic studies.…”

Section: Discussionmentioning

confidence: 76%

“…A functional transition occurs in the liver after birth, and most of the drug-metabolizing enzymes mature during this period. Changes in expression of some phase-I enzymes during liver maturation in humans have been reported, including cytochrome P450 (P450) (Stevens et al, 2003(Stevens et al, , 2008Koukouritaki et al, 2004;Croom et al, 2009), carboxylesterase (CES) (Yang et al, 2009;Zhu et al, 2009), paraoxonase (PON) (Cole et al, 2003;Huen et al, 2009), alcohol dehydrogenase (ADH) (Smith et al, 1971), and flavin monooxygenase (FMO) (Cherrington et al, 1998;Koukouritaki et al, 2002;Hines, 2006). The dynamic changes in the ontogenic expression of these genes are thought to be responsible for the substantial pharmacokinetic differences between newborns and adults, and this contributes to differences in therapeutic efficacy and adverse drug reactions in pediatric patients (Kearns et al, 2003;Blake et al, 2005;Hines, 2007Hines, , 2008Hines, , 2013).…”

Section: Introductionmentioning

confidence: 99%

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RNA-Sequencing Quantification of Hepatic Ontogeny of Phase-I Enzymes in Mice

et al. 2013

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Phase-I drug metabolizing enzymes catalyze reactions of hydrolysis, reduction, and oxidation of drugs and play a critical role in drug metabolism. However, the functions of most phase-I enzymes are not mature at birth, which markedly affects drug metabolism in newborns. Therefore, characterization of the expression profiles of phase-I enzymes and the underlying regulatory mechanisms during liver maturation is needed for better estimation of using drugs in pediatric patients. The mouse is an animal model widely used for studying the mechanisms in the regulation of developmental expression of phase-I genes. Therefore, we applied RNA sequencing to provide a "true quantification" of the mRNA expression of phase-I genes in the mouse liver during development. Liver samples of male C57BL/6 mice at 12 different ages from prenatal to adulthood were used for defining the ontogenic mRNA profiles of phase-I families, including hydrolysis: carboxylesterase (Ces), paraoxonase (Pon), and epoxide hydrolase (Ephx); reduction: aldo-keto reductase (Akr), quinone oxidoreductase (Nqo), and dihydropyrimidine dehydrogenase (Dpyd); and oxidation: alcohol dehydrogenase (Adh), aldehyde dehydrogenase (Aldh), flavin monooxygenases (Fmo), molybdenum hydroxylase (Aox and Xdh), cytochrome P450 (P450), and cytochrome P450 oxidoreductase (Por). Two rapidly increasing stages of total phase-I gene expression after birth reflect functional transition of the liver during development. Diverse expression patterns were identified, and some large gene families contained the mRNA of genes that are enriched at different stages of development. Our study reveals the mRNA abundance of phase-I genes in the mouse liver during development and provides a valuable foundation for mechanistic studies in the future.

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Section: Discussionmentioning

confidence: 76%

Section: Introductionmentioning

confidence: 99%

RNA-Sequencing Quantification of Hepatic Ontogeny of Phase-I Enzymes in Mice

et al. 2013

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“…50 This evidence of maternal exposure is even more relevant to the fetus, since human serum paraoxonase reaches adult levels only at approximately 12-18 months of postnatal life, leaving the fetus generally less protected regardless of PON1 genotypic status. 51 Another instance of environmental exposure continuously exceeding for several days the RfD set for diazinon was documented in a preschool child, whose household had received a pesticide application 3 days prior to toxicological screening. 52 Therefore, epidemiological studies clearly show that exposure to OPs can and indeed does occur in American households after spraying for pest control, and does involve pregnant women and small children.…”

Section: Markersmentioning

confidence: 99%

Paraoxonase gene variants are associated with autism in North America, but not in Italy: possible regional specificity in gene–environment interactions

et al. 2005

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Organophosphates (OPs) are routinely used as pesticides in agriculture and as insecticides within the household. Our prior work on Reelin and APOE delineated a gene-environment interactive model of autism pathogenesis, whereby genetically vulnerable individuals prenatally exposed to OPs during critical periods in neurodevelopment could undergo altered neuronal migration, resulting in an autistic syndrome. Since household use of OPs is far greater in the USA than in Italy, this model was predicted to hold validity in North America, but not in Europe. Here, we indirectly test this hypothesis by assessing linkage/association between autism and variants of the paraoxonase gene (PON1) encoding paraoxonase, the enzyme responsible for OP detoxification. Three functional single nucleotide polymorphisms, PON1 CÀ108T, L55M, and Q192R, were assessed in 177 Italian and 107 Caucasian-American complete trios with primary autistic probands. As predicted, Caucasian-American and not Italian families display a significant association between autism and PON1 variants less active in vitro on the OP diazinon (R192), according to case-control contrasts (Q192R: v 2 ¼ 6.33, 1 df, Po0.025), transmission/disequilibrium tests (Q192R: TDT v 2 ¼ 5.26, 1 df, Po0.025), familybased association tests (Q192R and L55M: FBAT Z ¼ 2.291 and 2.435 respectively, Po0.025), and haplotype-based association tests (L55/R192: HBAT Z ¼ 2.430, Po0.025). These results are consistent with our model and provide further support for the hypothesis that concurrent genetic vulnerability and environmental OP exposure may possibly contribute to autism pathogenesis in a sizable subgroup of North American individuals.

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“…Paraoxonase 1 (PON1) is an OP-hydrolyzing enzyme with high activity for detoxifying chlorpyrifos oxon (CPO) among many OPs (Geldmacher-von Mallinckrodt and Diepgen, 1988;Furlong et al, 1988). PON1 levels in children are often lowest at birth and can take up to 24 months or longer to reach adult levels (Augustinsson and Barr, 1963;Cole et al, 2003). The PON 192 genotype may be a factor in OP detoxification and therefore sensitivity Holland et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Lysophosphatidylcholine hydrolases of human erythrocytes, lymphocytes, and brain: Sensitive targets of conserved specificity for organophosphorus delayed neurotoxicants

Vose

Holland

Eskenazi

et al. 2007

Toxicology and Applied Pharmacology

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Brain neuropathy target esterase (NTE), associated with organophosphorus (OP)-induced delayed neuropathy, has the same OP inhibitor sensitivity and specificity profiles assayed in the classical way (paraoxon-resistant, mipafox-sensitive hydrolysis of phenyl valerate) or with lysophosphatidylcholine (LysoPC) as the substrate. Extending our earlier observation with mice, we now examine human erythrocyte, lymphocyte and brain LysoPC hydrolases as possible sensitive targets for OP delayed neurotoxicants and insecticides. Inhibitor profiling of human erythrocytes and lymphocytes gave the surprising result of essentially the same pattern as with brain. Human erythrocyte LysoPC hydrolases are highly sensitive to OP delayed neurotoxicants, with in vitro IC 50 values of 0.13-85 nM for longer alkyl analogs, and poorly sensitive to the current OP insecticides. In agricultural workers, erythrocyte LysoPC hydrolyzing activities are similar for newborn children and their mothers and do not vary with paraoxonase status but have high intersample variation that limits their use as a biomarker. Mouse erythrocyte LysoPC hydrolase activity is also of low sensitivity in vitro and in vivo to the OP insecticides whereas the delayed neurotoxicant ethyl n-octylphosphonyl fluoride inhibits activity in vivo at 1-3 mg/kg. Overall, inhibition of blood LysoPC hydrolases is as good as inhibition of brain NTE as a predictor of OP inducers of delayed neuropathy. NTE and lysophospholipases (LysoPLAs) both hydrolyze LysoPC, yet they are in distinct enzyme families with no sequence homology and very different catalytic sites. The relative contributions of NTE and LysoPLAs to LysoPC hydrolysis and clearance from erythrocytes, lymphocytes and brain remain to be defined.

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Expression of human paraoxonase (PON1) during development

Cited by 100 publications

References 45 publications

RNA-Sequencing Quantification of Hepatic Ontogeny of Phase-I Enzymes in Mice

RNA-Sequencing Quantification of Hepatic Ontogeny of Phase-I Enzymes in Mice

Paraoxonase gene variants are associated with autism in North America, but not in Italy: possible regional specificity in gene–environment interactions

Lysophosphatidylcholine hydrolases of human erythrocytes, lymphocytes, and brain: Sensitive targets of conserved specificity for organophosphorus delayed neurotoxicants

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