Effect of Antioxidant Supplementation on Pain, Antioxidant Profile and Oxidative Stress in Patients With Chronic Pancreatitis

INTRODUCTION Chronic pancreatitis (CP) is a progressive inflammatory disease of the pancreas accompanied by abdominal pain and in late stages, by exocrine and endocrine insufficiency. The etiology of CP include alcohol abuse, hereditary, ductal obstruction, tropical pancreatitis, systemic diseases (systemic lupus erythematosus and cystic fibrosis etc.), and idiopathic. Alcohol abuse accounts for 70-80% of cases of chronic pancreatitis in the West and about 40% in India. The intensity of injury depends on the duration and amount of alcohol consumed. Hereditary pancreatitis transmitted as an autosomal dominant trait accounts for a small subset of all cases of CP, and occurs due to mutation in cationic trypsinogen gene. Pancreatic duct obstruction may be secondary to trauma, pseudocysts, calcific stones or tumors and leads to obstructive CP (1). Tropical pancreatitis is a condition of unknown etiology that is seen predominantly in south India and other tropical areas of the World. Young patients are commonly affected with this disease. Cassava consumption had been proposed as an etiological factor due to its cyanogenic glycoside content however no epidemiological study has proved this hypothesis (2). Malnutrition has been suggested as an etiological factor in tropical pancreatitis. Idiopathic pancreatitis accounts for a substantial number of cases.

Many recent studies have emphasized a role for Reactive Oxygen Radicals (ROR) in the development of oxidative stress and hence inflammation in the pathogenesis of chronic pancreatitis. Increased oxidative stress probably results from increased exposure to xenobiotics. Xenobiotics are chemical substances present in the environment to which human beings are constantly exposed. It is conceivable that many of these xenobiotics are metabolized in pancreas that contains cytochrome P450 (CYP450) enzymatic system. The metabolism of xenobiotics occurs through two phases, Phase I and Phase II. Phase I metabolism may result in 'bioactivation' of the xenobiotics, in turn activating CYP system. Phase II involves attachment of biotransformed compound to a biological molecule that makes it more polar and thus easier to excrete. The metabolism of xenobiotics places an oxidative stress and can overwhelm the natural antioxidant defense of the body. The resultant production of the free radicals may play an important role in the pathogenesis of CP (2). Over induction of this enzyme can cause increased utilization of glutathione (GSH), which causes irreversible loss of glutathione. Moreover glutathione serves as a reservoir for cysteine/cystine required for disulphide synthesis for pancreatic digestive proteins. This further aggravates the situation. Three types of cytochrome enzymes are induced through xenobiotics. CYP2E1 has been specifically examined in the context of liver injury. CYP1A metabolizes smoke constituents and potent carcinogens such as benzo(a)pyrene. Cytochrome 3A is inducible by reactive oxygen species generated from aflatoxin B1. Alcohol, nicotine from cigarette smoke and other forms of tobacco consumption and industrial pollutants all are considered as xenobiotics and overwhelm the detoxification capacity of cytochrome CYP450 system (3). The CYP induction increases heme and heme-oxygenase thus buttressing the antioxidant defenses. The free radical peroxidation products may act as second messengers and block exocytosis leading to increased autophagy and crinophagy thus diverting the pancreatic enzymes into interstitium. This leads to degranulation of mast cells inducing inflammation mediated by chemotaxis. The synthesis of enzyme proteins in pancreas also produces H2O2, which also induces free radical production. Furthermore the depressed methionine trans-sulphuration pathway induces CYP as well. The free radicals generated from all these processes induce oxidative stress, which is implicated in damage to cell membranes due to lipid peroxidation. Above all, if the antioxidant levels of an individual are may be low due to either low intake or depletion during oxidative stress. Some studies also indicate that free radicals cause disintegration of antioxidative enzymes if over exposed to them.

However, the role of oxidative stress still not fully explained in that whether the oxidative stress is the cause of chronic pancreatitis or a consequence of it. This can be established by two observations: 1) If the oxidative stress is noted before the onset of disease and 2) If the disease symptoms are relieved by supplementation with antioxidants. Patients with alcoholic pancreatitis have been shown to have an increased oxidative stress. Supplementation with antioxidants hence decreases the production of such free radicals and may be beneficial to patients with CP (4).

A study by Braganza et al has shown that CP involves oxidative stress in-patients with CP (5). This was the first study to indicate the role of free radicals in the pathogenesis of chronic pancreatitis. However, the mechanism by which it occurs is still unclear. The preliminary studies show that malondialdehyde (MDA); a marker of peroxidation secondary to oxidative stress increases during CP.

In the present proposed study, the aim is to find out if there is increased oxidative stress in patients with CP and if supplementation with antioxidants relieves pain in them in order to establish a relationship between oxidant stress and pathophysiology of chronic pancreatitis.