Paraoxonase System and Importance in Human Body
Enzyme paraoxonase (PON) was first described in the early 1950’s (1, 2) and was introduced as an enzyme having both paraoxonase and arylesterase activity in 1995 (3). The genes encoding the PON family (PON1, PON2 and PON3) are all located on the long arm of chromosome 7 (7q21.3-q22.1) (4). PON1 and PON3 are expressed in the liver and after being excreted in the blood, they bind to high-density lipoproteins (HDL) (5, 6); PON2 is expressed widely in a number of tissues but is not present in the blood (7).
PON1 hydrolyzes certain organophosphates especially paraoxon, which is the metabolite of the insecticide parathion and the enzyme received its name from (8). It has also role in the metabolism of toxic oxidized lipids of both low-density lipoprotein (LDL) and HDL particles (9). PON1, synthesized in the liver and release to the circulation, is available in HDL structure and hydrophobic N-terminal of PON-1 can easily connect to the lipids of HDL (10). Mackness et al. showed that human PON1 could inhibit LDL oxidation in vitro, prevents formation of oxidized LDL and protects phospholipids in HDL from oxidation by inactivating LDL-derived oxidized phospholipids (11). These actions suggest that PON1 could prevent the accumulation of lipoperoxides in LDL and has a protective role against cardiovascular diseases and atherosclerosis (Figure 1).
Because of different habits and several polymorphisms of the PON1 gene, the serum levels of this enzyme vary between individuals (10). Some environmental, pharmacological or other factors may change the activity of PON1. The factors that induce the activity of PON1 are drugs such as statins, fibrates, aspirin, glucocorticoids, and phenobarbital, which are classical inducers of PON1 activity (1,12-14). Some enviromental chemicals abolish its activity (15). PON1 activity is also decreased by smoking, alcohol, fat-rich diet and aging (1-19). Very few studies had shown that PON1 activity is slightly higher in the female gender (14,20).
PON2 and PON3 both have antioxidant properties, hydrolyze aromatic and long-chain aliphatic lactones, but lack paraoxonase or arylesterase activities (21,22). As well as PON1, in vitro studies demonstrated that PON3 protects against LDL oxidation and inflammation (6) suggesting that PON3 may also have atheroprotective effect. Shih et al. reported that elevated PON3 expression significantly decreases atherosclerotic lesion formation and adipocity in male mice (23) which means PON3 may play an important role in protection against obesity and atherosclerosis.
More than 160 polymorphisms have been described to date in PON1, but two common polymorphisms in the coding region leucine(L)/methionine(M) at position 55 and glutamine(Q)/arginine(R) at position 192 were well-defined (24). Plasma PON1 activity in human population demonstrated a polymorphic distribution, therefore individuals with high, intermediate or low PON activity could be identified (20). Functional genomic analysis can be highly informative, as the determination of an individual’s PON1 activity is based on all polymorphisms that might affect the activity. Studies investigating the role of PON1 in cardiovascular disease have shown that PON1 status is a much better predictor of disease than PON1 genotype alone (25). Moreover, a study performed in Turkish population (26) has revealed that RR and LL genotypes of PON1 appear to be risk factors for the development of coronary artery disease (CAD) and also the RR genotype of PON1-192 was more common than the QQ genotype in patients with stenosis. In the same study, it was observed that PON1 55/192 variants were associated with the number of diseased vessels. On the other hand, another study performed in Turkish population (27) could not support these results and, the Nurses’ Health and Health Professionals Follow-up Study reported that the PON1 polymorphisms Q192 R and L55M were not associated with increased CAD risk (28). Thus, the relationship between PON 1 polymorphisms and CAD risk is still unclear.
After the relationship between PON1 enzyme and lipid peroxidation has been described, new studies were performed to investigate the association between PON1 activity and some endocrine diseases like obesity, thyroid diseases and diabetes. In this review, we aimed to highlight the importance of PON1 in the endocrine system and the association of this enzyme with some clinical diseases.
PON1 Activity in Diabetes
PON1 activity has been studied in patients with metabolic syndrome and insulin resistance, the first step to type 2 diabetes, and some contradictions were found between the studies performed in non-diabetic subjects. In non-diabetic Swiss population (n=574; 429 with CAD), the significantly reduced serum PON1 concentrations and activities were associated with metabolic syndrome defined according to the WHO guidelines (29). Moreover, Yamada A et al. have shown that there was a positive correlation between HOMA index and HDL-corrected PON1 activity in 237 non-diabetic Japanese subjects, which was an unexpected result (30). Same in Turkish population, PON1 activities were not different between non-diabetic subjects with and without metabolic syndrome (31). Additionally, Beer S et al. (32) found that PON1 activities and concentrations were lower in diabetic patients compared to subjects with impaired fasting glucose and controls, although glucose intolerant patients had similar PON1 values as non-diabetics. In the same study, significantly low serum PON1 concentrations in the postprandial period were demonstrated, attributed to postprandial hypertriglyceridaemia, whereas the decrease in PON1 activity was not statistically significant. There was no difference in the postprandial PON1 response between diabetic and non-diabetic groups. In another study (33), PON1 activity was not significantly altered compared with normoglycemic controls although oxLDL levels were significantly higher in glucose intolerant and newly diagnosed subjects (33). All these studies suggest that PON1 activity loss may occur later in the course of diabetes mellitus and hyperglycemia, rather than in the stage of insulin resistance.
Serum PON1 activity has been found significantly decreased in type 1 and type 2 diabetes compared to the healthy control subjects (34, 35, 36). Ferretti et al. reported that PON1 activity was significantly lower in type 1 diabetic patients compared to healthy controls and that the decreased ability of HDL to protect erythrocyte membranes could be related to lipid composition of HDL and to this low PON1 enzyme activity (34). Another study revealed that PON1 activity was decreased in type 1 and type 2 diabetic patients compared to non-diabetic control subjects although PON serum levels were not significantly different. In the same study, the authors reported that triglyceride levels in both types of diabetes were higher than in controls. As different from type 1 diabetes, HDL and apolipoprotein (apo) A-I levels have found to be lower in type 2 diabetic patients (37).
There is a contradiction in the literature about the correlation between HbA1c and PON1 activity. A negative correlation was found in both types of diabetes (36) although no significant association was reported between HbA1c and PON1 activity in a study performed in type 1 diabetes patients (34). There was also a negative correlation between PON1 activity and presence of vascular complications (36). The lower serum PON1 activity was found in diabetic patients with macrovascular than in those with microvascular complications. In a recent study (38), reduced PON1 activity in type 2 diabetic patients was found to be associated with a significant increase in the risk of cardiovascular disease (CVD) which leads to the conclusion that PON1 activity could be a predictor of CVD in type 2 diabetes (38). Both PON1 and arylesterase enzyme activities were lower in diabetic foot patients compared to healthy control subjects (39). Studies investigating the relationship between diabetes complications and PON1 polymorphisms have shown different results. Flekac et al. reported that L55M and Q192R polymorphisms are more common in diabetes and are associated with macroangiopathy (36). PON1-55MM and PON1-192QQ genotypes were associated with poorer diabetes control than LL and RR genotypes. Better diabetes control was found in patients with LL genotype than with MM and similarly, in those with RR genotype vs. QQ (P<0.05). Chiu KC et al. have shown that L55M polymorphism, not Q192M, was an independent determinant for beta-cell function in glucose-tolerant whites (40). In Turkish population, PON1-R192 variant was found as an independent genetic risk factor more than three times in the development of complications in diabetes (41) and RR genotype may be a risk factor for cardiac complications in type 2 diabetes patients (42). Although association of LL genotype and the development of diabetic retinopathy has been reported by Mackness et al. (43), this relationship could not be confirmed in Turkish population (42). PON1 activity was significantly low in patients with non-insulin dependent diabetes mellitus and retinopathy compared to patients without complication, but was not different between patient with and without proteinuria (44). The authors have reported that logistic analysis showed that serum PON activity was one of the factors for retinopathy. Serum PON1 activity in diabetic patients with neuropathy was notified significantly lower than in patients without diabetic neuropathy (37).
PON1 Activity in Thyroid Disease
Patients with thyroid dysfunction are more prone to oxidative stress, and may display enhanced LDL oxidation (45). A study performed in Turkish population has shown that serum PON activity and insulin sensitivity index (ISI) were significantly lower in hyperthyroid patients before treatment and were negatively correlated with serum TT4 and TT3 levels, whereas both were increased after restoration of euthyroidism by using propylthiouracil (PTU); HDL cholesterol level was increased compared to baseline (46). In euthyroid multinodular goitre (MNG) patients, HDL cholesterol level, ISI and PON activity were decreased with TSH-suppressing L-T4 therapy. This result indicates that a significant decrease in PON activity was associated with decreased insulin sensitivity and increased oxidative stress in both endogenous hyperthyroidism and iatrogenic thyroid hormone excess. In a case-control study, 24 hyperthyroid patients and healthy controls were compared before and after methimazole (20-30 mg/d) therapy (47). Significantly lower serum PON1 activity was reported in hyperthyroid patients before treatment compared to controls, and enzyme activity had increased when the patients became euthyroid. The authors suggest that reduced PON1 activity in thyrotoxicosis might predispose lipids to oxidation. Same authors also found significantly reduced PON1 activity and changes of lipid levels in ninety-nine patients with thyroid dysfunction (49 hypothyroid and 50 hyperthyroid) when compared with 2 separate age- and sex-matched control groups (48). Thus, increased LDL-C oxidation in thyroid dysfunction can be attributed to reduced PON1 activity.
PON1 Activity in Dyslipidemia
The positive correlation between PON1, HDL cholesterol and apo A-I is well-known (37). HDLs are classified according to their content of major apolipoproteins: apo A-I and apo A-II. HDL-cholesterol subfraction distribution of PON1 has not been clearly established, although correlations of serum PON1 with apo A-I and apo A-II have been noted. The rise in apo A-I, which plays a protective role against atherosclerosis, was associated with an increase in serum PON1 concentration. On the other hand, the role of apo A-II is less understood and human apo A-II has generally been found to be proatherogenic (49). In vitro displacement of PON1 by human apo A-II at physiological concentrations could explain the observation that PON1 was mostly found in HDL particles containing apo A-I but not apo A-II, and thus, the lack of anti-atherogenic properties of apo A-II-enriched HDL (50). Zech et al. have reported that PON1 may first bind to smaller HDL3 particles and then transform into a larger HDL2 particle (51). Following studies performed with both gel filtration and electron microscopic measurements confirmed this suggestion and PON1 would seem to be present in larger sized HDL2 particle (52-54).
Some studies show that lipid-lowering treatments improve PON1 serum activity. In a recent study (55) performed in 164 patients with type IIb hypercholesterolaemia, three months of statin treatment (atorvastatin 10mg/day, simvastatin 10/20mg/day and fluvastatin 80mg/day) significantly increased the PON activity in the 3 statin-treated groups compared to controls. Paragh et al. reported that three-month treatment with micronized fenofibrate 200mg/d on 52 patients with coronary heart disease and type IIb hyperlipidemia significantly increased serum PON activity (p<0.05) and improved antioxidant status (56). Oppositely, in another study on normolipidemic rats, fenofibrate treatment dose-dependently decreased plasma PON1 activity by 20% to 40% (57). In type 2 diabetic patients, gemfibrozil (GEM) 600mg/bid for 3 months increased PON1 activity (58) although no difference was observed in PON1 activity with GEM (600mg/bid) and bezafibrate (400mg/d) treatments for 8 weeks in type IIb hyperlipidemic patients (59). Macan M et al. (60) reported that after GEM treatment, plasma PON1 activity significantly reduced in rats on high-sucrose diet or on control diet compared to rats on diet-only therapy. In conclusion, the decreasing effect of fenofibrate on PON1 activity may be potentially an adverse effect, which could be masked by the positive changes in plasma lipid profile.
PON1 gene therapy may play a role in the management of dyslipidemia and liver diseases in the future. Injection of plasmid containing the human PON1 gene via rat tail vein could prevent dyslipidemia and hepatic lipid accumulation, by increasing antioxidant SOD and decreasing serum levels of LDL, total cholesterol, triglyceride and MDA. These results indicate that gene therapy with pcDNA/PON1 might be an effective treatment for hyperlipidemia and liver diseases like hepatosteatosis (61).
PON1 Activity in Obesity
Obesity is a world-wide problem which is associated with several alterations in the lipid metabolism. The greater risk of cardiovascular disease in obese patients is probably associated with changes in lipoprotein levels and composition (62). It has been observed in several studies that oxidative stress is increased in obese subjects compared with healthy controls (63); Ferretti G et al. reported significantly lower PON activity in obese subjects compared with control subjects (64). In another study, a relationship was found between HDL-PON and lipid hydroperoxides in HDL and LDL of control and obese subjects, which suggest that subjects with lower PON activity are more exposes to oxidative damage. These results confirm that obesity is associated with oxidative damage of lipoproteins and may explain the increased cardiovascular risk in obese people.
In a controlled multi-center study, 78 obese patients received orlistat 120 mg tid with calorie-restricted diet and 61 patients were treated with diet only for 6 months (65). At the end of the study, PON1 activity significantly increased in both groups, but the changes in PON activity and PON/HDL ratio were higher in orlistat+diet group compared to diet-only group.
PON1 Activity in Polycystic Ovary Syndrome
Firstly, Dursun P et al. have measured serum PON1 activity in Turkish women with PCOS and found that PON1 activity was significantly lower in the PCOS group compared to the controls, whereas HOMA index was significantly higher in the PCOS group (66). There was a significant negative correlation between serum total testosterone levels and serum PON1 activity. Those results have been supported by Fenkci IV et al. in 2007 (67). Recently, a study performed in Saudi women with PCOS showed that PON1 activity and anti-oxidant status (by total antioxidant capacity and malondialdehyde) were significantly decreased compared with controls (68). These findings suggest that decreased PON1 activity in PCOS patients may contribute to insulin resistance and atherosclerotic heart disease. San Millan et al. found that homozygosity for -108T alleles was more prevalent in PCOS patients compared with healthy controls (69). After this study, same authors have shown that women homozygous for -108T alleles presented with reduced PON activity compared with women carrying one or two -108C alleles (70).Thus, they suggested the PON1-108C/T polymorphism, and not PCOS, is an important determinant of serum PON activity, at least in premenopausal Spanish women.
PON1 Activity in Osteoporosis
The relationship between osteoporosis and atherosclerosis is still unknown. In 97 healthy postmenopausal Turkish women, no correlation was observed between PON1 activity and bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DEXA) (71). Same in postmenopausal Japanese women, serum PON1 activity was not related to BMD of both lumbar spine and femoral neck (72). On the other hand, the authors have shown that G192R and L55M genotypes of PON1 were associated with BMD, whereas there was no significant relationship between polymorphisms of PON1 gene and BMD in premenopausal women or in men.
PON1 Activity in Acromegaly
Patients with acromegaly have an increased mortality rate due to cardiovascular causes. To date, only one study, from Argentina, evaluated active acromegalic patients (n=15) for oxLDL levels and oxidative stress markers in comparison with age- and gender-matched healthy controls (73). Increased oxLDL levels were detected in patients with acromegaly. Serum PON1 activity was lower in patients than in controls, but the difference was not statistically significant.
In conclusion, an anti-oxidant enzyme PON1 prevents formation of oxidized LDL and protects phospholipids in HDL from oxidation by inactivating LDL-derived oxidized phospholipids. Serum PON1 levels decrease in some endocrine diseases accompanied by high oxidative stress like obesity, uncontrolled diabetes, thyroid dysfunctions, dyslipidemia, polycystic ovary and acromegaly. Significantly reduced serum PON1 concentrations and activities were associated with metabolic syndrome and obesity, which are the first step of diabetes, type 1 and type 2. Serum PON1 activity was found to be lower in diabetic patients with macrovascular than in those with microvascular diabetic complications. Moreover, it was significantly reduced in both hyperthyroidism and hypothyroidism. PON1 level is positively correlated with HDL cholesterol and negatively with LDL cholesterol. Serum PON1 level and activity were significantly low in PCOS and acromegaly patients, while the change in PON1 activity was not associated with osteoporosis. More than 160 polymorphisms have been described to date in PON1 gene, however, there is still not enough evidence to support the hypothesis that relationship exists between endocrine diseases and a specific polymorphism in PON gene.
Address for Correspondence: Özlem Tarçın, Başkent University Hospital, Department of Endocrinology and Metabolism, İstanbul, Turkey
Phone: +90 216 450 51 44 E-mail: firstname.lastname@example.org Recevied: 01.02.2011 Accepted: 01.02.2011
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