Role of Reactive Oxygen Species in Mercapto-Methylimidazole-Induced Gastric Acid Secretion and Stress-Induced Gastric Ulceration

The objective of the present study is to delineate the role of reactive oxygen species in drug-induced gastric hyperacidity and stress-induced gastric ulceration. We reported earlier that mercaptomethylimidazole (MMI), an antithyroid drug, induces gastric acid (HCl) secretion partially through H2receptor activation of the parietal cell by histamine release and partially through an intracellular mechanism. While studying the latter, MMI-induced acid secretion was found to correlate well with the inactivation of the peroxidase, an important H2O2metabolizing enzyme of the mucosa. MMI activates the isolated parietal cell for acid secretion, which is sensitive to omeprazole. Peroxidase and catalase activity of the isolated cell is also irreversibly inactivated by MMI. It thus creates a favourable condition for endogenous accumulation of H2O2. Acid secretion by gastric gland preparation or isolated gastric mucosa is stimulated by exogenous H2O2, which is inhibited by omeprazole. Studies indicate that H2O2inactivates the prostaglandin synthetase and removes the inhibitory influence of prostaglandin on acid secretion. MMI thus stimulates acid secretion not only through H2, receptor activation but also through the stimulation of the parietal cell by intracellular generation of H2O2following inactivation of the peroxidase-catalase system. Among the various factors responsible for gastric ulceration, stress was found to cause severe haemorrhagic lesions mainly through oxidative damage of the mucosa as indicated by increased lipid peroxidation, increased protein carbonyl content, and decreased glutathione level. The severity of ulcer correlates well with the time-dependent induction of superoxide dismutase and inactivation of peroxidase, a condition favourable for accumulation of endogenous H2O2. Desferrioxamine prevents stress ulcer, indicating involvement of transition metal ion in the process. Studies indicate that severity of stress ulcer is dependent on the concurrent generation of hydroxyl radical (•OH) formed through metal-catalysed Haber-Weiss reaction between O2-and H2O2

Nonsteroidal Anti-Inflammatory Drugs Inhibit Gastric Peroxidase Activity.

The peroxidase activity of the mitochondrial fraction of rat gastric mucosa was inhibited with various nonsteroidal anti-inflammatory drugs (NSAIDs) in vitro. Indomethacin was found to be more effective than phenylbutazone (PB) or acetylsalicylic acid (ASA). Mouse gastric peroxidase was also very sensitive to indomethacin inhibition. Indomethacin has no significant effect on submaxillary gland peroxidase activity of either of the species studied. Purified rat gastric peroxidase activity was inhibited 75% with 0.15 mM indomethacin showing half-maximal inhibition at 0.04 mM. The inhibition could be withdrawn by increasing the concentration of iodide but not by H202. NSAIDs inhibit gastric peroxidase activity more effectively at acid pH (pH 5.2) than at neutral pH. Spectral studies showed a bathochromic shift of the Soret band of the enzyme with indomethacin indicating its interaction at or near the heme part of the enzyme

Ecto-ATPase

An ecto-adenosine triphosphatase (E.C. 3.6.1.4 ATP-phosphohydrolase) is shown to be localised on the outer surface of varieties of cell membrane. The enzyme is different from the ATPase involved in biological energy transduction and ion transport mechanism. The characteristic of the enzyme lies in having a very broad substrate specificity and is inhibited by EDTA and higher concentration of ATP. The enzyme is dependent on bivalent metal ions, Mg++ or Ca++ for its optimum activity. The enzyme is highly sensitive to SH-reagents but insensitive to inhibitors of mitochondrial ATPase or Na+-K+-ATPase. The possible functions of the enzyme in being oriented outside the cell membrane is discussed

Turmeric and curcumin: biological actions and medicinal applications

Turmeric (Curcuma longa) is extensively used as a spice, food preservative and colouring material in India, China and South East Asia. It has been used in traditional medicine as a household remedy for various diseases, including biliary disorders, anorexia, cough, diabetic wounds, hepatic disorders, rheumatism and sinusitis. For the last few decades, extensive work has been done to establish the biological activities and pharmacological actions of turmeric and its extracts. Curcumin (diferuloylmethane), the main yellow bioactive component of turmeric has been shown to have a wide spectrum of biological actions. These include its antiinflammatory, antioxidant, anticarcinogenic, antimutagenic, anticoagulant, antifertility, antidiabetic, antibacterial, antifungal, antiprotozoal, antiviral, antifibrotic, antivenom, antiulcer, hypotensive and hypocholesteremic activities. Its anticancer effect is mainly mediated through induction of apoptosis. Its antiinflammatory, anticancer and antioxidant roles may be clinically exploited to control rheumatism, carcinogenesis and oxidative stress-related pathogenesis. Clinically, curcumin has already been used to reduce post-operative inflammation. Safety evaluation studies indicate that both turmeric and curcumin are well tolerated at a very high dose without any toxic effects. Thus, both turmeric and curcumin have the potential for the development of modern medicine for the treatment of various diseases

Purification and Characterization of a Soluble Peroxidase of Rat Preputial Gland: Comparison with Lactoperoxidase

A highly active ,soluble peroxidase (donor: H202 oxidoreductasc EC I.i !.i.7) has bccn purified from the preputial gland of the rat by hydroxylapatitc chromatography, ammonium sulfate fraclionation, Sephadex gel filtration and affinity chromatography on con A-Sepharosc. The enzyme shows apparent homogcneity when analysed by acid and alkaline-PAGE. Its molecular, spectral, kinetic and catalytic properties were compared with those of bovine lactoperoxidase (LPO). Preputial gland pcroxidase (PPO) is a glycoprotein of molecular weight of 711-73 kDa slightly lower (78 kDa) than that of LPO. Using isoelectric focussing, PPO was resolved into eight different closely spaced protein species spanning a pl range of 5.4 to 6.4, while LPO focusscs into several closely spaced protein bands in the pl range 8.5-9.3. PPO is similar to LPO in its spectral (Soret) and some kinetic properties, but it differs significantly from LPO in substrate (H,_O2) tolerance and substrate inactivation. PPO also differs from LPO in showing differential inactivation by SDS. Both enzymes arc glycoproteins and although concanavalin A (con A) showed a variable interaction with both enzymes, wheat germ agglutinin interacted specifically with LPO only. We suggest that PPO, the ~cretory peroxidase of the preputial gland, differs significantly from LPO in its molecular and catalytic propertie

Partial purification and characterization of the phosphate transporter from bovine heart mitochondria

A highly active phosphate transporter was extracted with octylglucoside from bovine heart submitochondrial particles that were first partially depleted of other membrane components. It was then partially purified by ammonium sulfate fractionation. After reconstitution of the transporter into liposomes prepared with a crude mixture of soybean phospholipids, the P<SUB>i</SUB>/OH exchange, but not the P<SUB>i</SUB>/P<SUB>i</SUB> exchange, was stimulated three- to fourfold by valinomycin and nigericin in the presence of K<SUP>+</SUP>. Both P<SUB>i</SUB>/OH and P<SUB>i</SUB>/P<SUB>i</SUB> exchange activities were sensitive to mercurials and other SH reagents. The rutamycin-sensitive ATPase complex from mitochondria was reconstituted together with the phosphate transporter and adenine nucleotide transporter into liposomes. After inhibition of externally located ATPase, the hydrolysis of ATP was sensitive to atractyloside and mersalyl