Genetic Polymorphism in Paraoxonase 1 (PON1): Population Distribution of PON1 Activity

Abstract

Paraoxonase-1 (PON1) is a serum esterase that hydrolyzes the activated oxon form of several organophosphates. The central role of PON1 in detoxification of organophosphate (OP) pesticides was demonstrated in knockout mouse studies, suggesting that human variability in PON1 needs to be considered in health risk assessments involving exposure to these pesticides. The current analysis focused on two genetic loci in which polymorphisms demonstrated to affect PON1 activity. Detailed kinetic studies and population studies found that the *192Q (wild type) allele is more active toward some substrates (such as sarin, soman, and diazoxon) and less active toward others (such as paraoxon or chlorpyrifos) relative to the variant *192R allele. Another allele that affects activity is *55M; PON1 enzyme quantity, rather than specific activity or substrate preference, is altered. The *192R variant occurs commonly with a frequency of 25-64% across the populations analyzed. The *55M allele is less common, occurring in 5-40% of individuals depending upon the ethnic group studied. These activity and allele frequency data were incorporated into Monte Carlo simulations in which the frequency of both variant alleles was simultaneously modeled in Caucasian, African American, and Japanese populations. The resulting Monte Carlo activity distributions were bimodal for the substrate paraoxon with approximately fourfold differences between low- and high-activity modal medians. Differences in activity between total population median and 1st percentile were five- to sixfold. When sarin metabolic variability was simulated, the population distributions were unimodal. However, there was an even greater degree of interindividual variability (median to 1st percentile difference >20-fold). These results show that the combined effects of two PON1 allelic variants yielded a population distribution that is associated with a considerable degree of interindividual variability in enzyme activity. This indicates that assessments involving PON1 substrates need to evaluate polymorphism-related variability in enzyme activity to display the distribution of internal doses and adverse responses. This may best be achieved via physiologically based pharmacokinetic (PBPK) models that input PON1 activity distributions, such as those generated in this analysis, to simulate the range of oxon internal doses possible across the population.

Lactonase activity and status of paraoxonase 1 in Chinese women with polycystic ovarian syndrome

“…The frequency of the 192R allele among Chinese subjects in the current study (60%) is higher compared with other populations, such as Greek (9.5%), Caucasians (24-31%), Asian Indian (31%), and Hispanic Americans (42-46%), and similar to Korean (60%) and Japanese (59-66%) (57,58). The frequency of the 55M allele was 4% in this study carried out in the Chinese population.…”

“…It was shown to be higher in Caucasians (26-38%), and similar to Korean (3%), but slightly higher in Japanese (9-10%) (58). The frequency of the K108T allele among Chinese subjects in this study (43%) was lower compared with Caucasians (50-54%) (59), and similar to Greek (43.5%) (57), but higher compared with African Americans (15.5%) and Hispanics (35%) (58). Interestingly, the PON1 192RR genotype, but not K108TT genotype, was associated with PCOS in our previous studies (34,37).…”

Serum PON-1 Activity but not Q192R Polymorphism is Related to the Extent of Atherosclerosis

“…Conflicting results were also obtained from studies assessing the effect of genotype on enzyme activity. It has been shown that PON1 192R hydrolyzes paraoxon more efficiently while PON1 192Q has higher catalytic activity towards soman and sarin 35) . On the other hand, both isozymes hydrolyze phenyl acetate at the same rate.…”

Evidence for association between paraoxonase 1 gene polymorphisms and polycystic ovarian syndrome in south-west Chinese women

“…In addition, the allele frequencies for PON1 polymorphisms differ among ethnic groups (12,18,30). Environmental factors such as smoking, high-fat diet, and consumption of antioxidants may also affect PON1 status on HDL in circulation or PON1 expression (42).…”

“…Chen et al (29) studied a relationship between 23 single nucleotide polymorphisms in the PON1 gene and PCOS in north Chinese women in a genome-wide association study, but the study did not include rs662 and rs854560 sites. As genotype and allele frequencies for PON1 gene polymorphisms differ greatly among ethnic groups (12,30), it is important to address whether there are any relationships between the 192Q/R and the 55L/M polymorphisms and PCOS in Chinese women. Therefore, in this study, we investigated the genotype distribution of PON1 192Q/R and 55L/M polymorphisms in women from healthy and PCOS populations in a well-characterized Chinese population using relatively large sample sizes (610 cases and 503 controls).…”