Paraoxonase 3: Structure and Its Role in Pathophysiology of Coronary Artery Disease.

Spanning three decades in research, Paraoxonases (PON1) carried potential of dealing with neurotoxicity of organophosphates entering the circulation and preventing cholinergic crisis. In the past few years, the Paraoxonase multigene family (PON1, PON2, PON3) has been shown to play an important role in pathogenesis of cardiovascular disorders including coronary artery disease (CAD). The PON genes are clustered in tandem on the long arm of human chromosome 7 (q21, 22). All of them have been shown to act as antioxidants. Of them, PON3 is the least studied member as its exact physiological substrate is still not clear. This has further led to limitation in our understanding of its role in pathogenesis of CAD and development of the potential therapeutic agents which might modulate its activity, expression in circulation and tissues. In the present review, we discuss the structure and activity of human PON3 enzyme and its Single nucleotide variants that could potentially lead to new clinical strategies in prevention and treatment of CAD.

Serum Paraoxonase (PON1) Activity in North-West Indian Punjabi's with Acute Myocardial Infarction.

Human serum paraoxonase-1 (PON1), an enzyme on HDL prevents oxidation of LDL thereby preventing the development of atherosclerosis. Studies done so far have lead to conflicting results. As studies are lacking in North-West Indian Punjabi's, a distinct ethnic group with high incidence of coronary artery disease, we determined PONase activity in this population. It has been postulated that sudden lowering of serum PONase may lead to precipitation of acute myocardial infarction. We determined serum PONase activity and lipids in 100 patients each of AMI (within 24 h of onset), stable CAD and 100 age and sex matched healthy controls. These were again determined after 6 weeks in AMI patients. The mean serum PONase activity was lowest in AMI patients (23.26 U/ml) followed by stable CAD patients (102.0 U/ml) where as in controls was highest (179.8 U/ml). In patients with AMI, activity was significantly higher at 6 weeks as compared to that after acute event (49.39 %; p < 0.05). Sudden lowering of serum PONase activity in a population which already has lower activity may be one of the risk factors for development of AMI.

Paraoxonases: structure, gene polymorphism & role in coronary artery disease.

Paraoxonases (PONs) i.e. PON1, PON2, PON3 are basically lactonases. Of these, PON1 in addition has an efficient esterase activity and can hydrolyze organophosphates. The PONs prevent low density lipoprotein cholesterol (LDL-C) from peroxidation, thereby preventing atherosclerosis. The PON1 is exclusively associated with high density lipoprotein cholesterol (HDL-C) and its antioxidant activity is largely attributed to PON1 located on it. At present, PON1 status i.e. its activity and concentration, is considered to be more important than polymorphism alone, in prevention of coronary artery disease (CAD). Its activity has been found to be affected by a number of pharmacological agents, diet and other factors, thereby becoming a promising target for pharmacological intervention. The PON2 prevents cell mediated lipid peroxidation. However, little is known about the role of PON3. This review describes the structure, gene polymorphism, and factors affecting the activity of PONs, and their role in prevention of CAD.

Hyperamylasemia and acute pancreatitis following anticholinesterase poisoning.

A prospective study was undertaken to find the incidence of hyperamylasemia and acute pancreatitis in patients with anticholinesterase poisoning. This was done by serial estimation of total serum amylase and pancreatic imaging by ultrasonography and confirmed, if necessary, by computerized tomography. Anticholinesterase poisoning was caused by either ingestion or accidental exposure to organophosphates or carbamates; it was diagnosed when patients presented with features of cholinergic crisis, depressed serum butyrylcholinesterase activity of >50% and showed improvement following administration of atropine alone or atropine and 2-PAM. All the patients admitted with anticholinesterase poisoning between July 2001 and June 2005 were prospectively studied for elevated serum amylase. The serum amylase levels were estimated daily up to 10 days in survivors and in nonsurvivors till they survived. Ultrasonography of the abdomen was carried out in all to find swelling of the pancreas. Computerized tomography was undertaken in those who had a swollen pancreas or whose serum amylase levels were elevated significantly (> or =800 S.U). Of the 86 patients enrolled, 79 were taken up for analysis as data were incomplete in 7. Of the 79 patients, serum amylase was found to be elevated that is, >200 S.U. in 37 patients (46.95%). In three patients it was 800 S.U. One of them showed swollen pancreas on ultrasonography, which was confirmed by computerized tomography. This patient had ingested propoxyfur. In the other two patients, evidence of acute pancreatitis was not observed (on autopsy in one who died and on imaging in the other who survived). They had ingested chlorpyrifos. There was no significant correlation between the nature of the compounds (organophosphate or carbamates), inhibition of serum BUChE at admission, duration and severity of cholinergic syndrome and increase and time course of increase in serum amylase. Except for fenthion, significant persistent increase in serum amylase was not observed with individual compounds. The other associated abnormalities were polymorphonuclear leukocytosis (TLC >11,000/cumm) in all 37 patients who had elevated amylase, hyperglycemia (6/37) and, elevated transaminases (6/37). Mild elevation of serum amylase is common in patients with anticholinesterase poisoning. However, acute pancreatitis is rare.

Cytochrome-c oxidase inhibition in 26 aluminum phosphide poisoned patients.

INTRODUCTION: Aluminum phosphide (ALP) is used worldwide to fumigate grain. ALP poisoning, though reported from different parts of world, is most common in north, northwest and central India. In the presence of moisture, ALP liberates phosphine, which is highly toxic. The mechanism of action of phosphine is not known though experimental studies show that it inhibits cytochrome-c oxidase leading to inhibition of mitochondrial oxidative phosphorylation. PATIENTS AND METHODS: We estimated cytochrome-c oxidase activity in platelets of patients who had ingested ALP and compared them with those in healthy controls and in patients with shock due to other causes (cardiogenic shock, septic shock and hemorrhagic shock). RESULTS: After analysis of variance using Kruskal-Wallis test followed by Mann Whitney U test, significant inhibition of cytochrome-c oxidase activity could be found in ALP-poisoned patients compared to healthy controls (z = -5.513, p < 0.001) and in patients with shock due to other causes (z = -2.344; p < 0.05). There was no significant difference in inhibition in those who survived ALP poisoning compared to those who died from ALP poisoning (t = 0.02768; p > 0.05). CONCLUSION: Though inhibition of cytochrome-c oxidase in platelets does not have prognostic value, it suggests that interruption of mitochondrial oxidative phosphorylation as a result of cytochrome-c oxidase inhibition may lead to multi-organ dysfunction and therapeutic strategies to maintain enzyme activity may help in managing these patients.