Developmental Changes in PON1 Enzyme Activity in Young Children and Effects of PON1 Polymorphisms

Abstract

BackgroundParaoxonase 1 (PON1) is an enzyme that detoxifies activated organophosphorus pesticides (OPs) and is also involved in oxidative stress pathways.ObjectivesPON1 activity in newborns is lower than in adults, but the ontogeny of PON1 activity is poorly characterized in young children. We examined the effects of age and PON1 genotype on enzyme activity in a birth cohort of Mexican-American children.MethodsWe determined three substrate-specific measures of PON1 activity in 1,143 plasma samples collected longitudinally from 458 children at five time points from birth through 7 years of age, and genotyped PON1 polymorphisms at positions 192 and –108 in these children.ResultsContrary to previous reports that PON1 activities plateau by 2 years of age, we observed an age-dependent increase in all three PON1 measures from birth through 7 years of age (p < 0.0001). The PON1192 genotype significantly modified the effect of age on paraoxonase (POase) activity (p < 0.0001) such that increases in enzyme activity with age were influenced by the number of R alleles in a dose-dependent manner. Children with the PON1-108CC192RR diplotype had significantly higher mean PON1 activities and also experienced steeper increases of POase activity over time compared with children with the PON1-108TT192QQ diplotype.ConclusionsLower levels of the PON1 enzyme, which is involved in protection against OPs and oxidative stress, persist in young children past 2 years of age through at least 7 years of age. Future policies addressing pesticide exposure in children should take into account that the window of vulnerability to OPs in young children may last beyond infancy.

Association between paraoxonase 1 (PON1) enzyme activity, PON1 C(−107)T polymorphism, nutritional status, and lipid profile in children

“…Similar results have been reported by other studies [18]. Moreover, in the CHAMACOS Mexican cohort, the authors observed that the average PON1 activity in children raised from age five to seven was similar between boys and girls [19].…”

“…The genotypic and allelic frequencies of the studied sample were also similar to those found in Mexican children [19], in contrast to observed in Caucasian adult populations, where the C and T alleles frequencies were close to 50% [8,20].…”

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

“…A study showed that lower levels of PON1 enzyme persisted in young children till at least 7 years of age (Huen et al, 2009), which was similar to the ontogenic pattern of Pon1 mRNA expression in mice. Another group found that the plasma PON1 activity in mice reached a plateau in 3 weeks after birth (Li et al, 1997), which is dmd.aspetjournals.org similar to our data of Pon1 mRNA expression in mouse livers (Fig.…”

“…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).…”

Functionality of HDL: Antioxidation and Detoxifying Effects

“…Serum concentrations of the enzyme, as well as certain polymorphisms affecting activity, appear important for risk prediction (Androutsopoulos et al 2011;Costa et al 2013). Consequently, children may be more sensitive to environmental OPs since they have reportedly lower PON1 levels than adults (Huen et al 2009). Finally, its impact on environmental toxins, as well as its antioxidant function, has led to suggestions that PON1 is linked to neurological disorders (Androutsopoulos et al 2011), an area that requires considerably more research.…”