Sa1863 L-Cysteine Slow-Release Capsule Formulation in Prevention of Gastric Carcinogenesis Associated With Atrophic Gastritis

Abstract

INTRODUCTION: Atrophic gastritis (AG) with concomitant acid-free or hypochlorhydric stomach and Helicobacter pylori infection are the two most important risk factors for gastric cancer. Gastric mucosa, many microbes colonizing acid-free stomach and H. pylori strains possess alcohol dehydrogenase activity capable of locally producing acetaldehyde (ACH) from ethanol. ACH produced from ethanol in oral cavity contributes to gastric ACH exposure via saliva. Limited capacity of mucosal cells and microbes to eliminate ACH, results in enhanced exposure of gastric mucosa to the carcinogenic actions of ACH. ACH associated with alcoholic beverages has been classified as carcinogenic (Group 1) to humans by IARC/ WHO. Capsule that slowly releases L-cysteine in the stomach converting ACH to inactive 4-methyltiazolidine-2-carboxylic acid (MTCA) has been recently implicated in prevention of gastric carcinogenesis among patients with AG. AIMS: To assess the production of ACH and MTCA in the stomach of AG patients following an exposure to 15% ethanol, with or without administration of L-cysteine. METHODS: Seven H.pylori positive patients, selected among 42 subjects with biopsy-confirmed AG, and fasting serum levels of pepsinogen (PG) I 10 pmol/L participated in the study. In a single-blinded fashion and on two separate days, patients were intubated with a nasogastric tube and exposed to15 % ethanol (0.3g/kg) and randomly 200 mg of L-cysteine or placebo. Gastric juice samples (5mL) were drawn every 20 min over a period of 4 hours and analyzed for pH and ACH-, ethanol-, L-cysteineand MTCA-concentrations. ACH and ethanol were analyzed by headspace gas chromatography and L-cysteineand MTCA-levels by liquid chromatography coupled to a triple-quadropole mass spectrometer. RESULTS: After intake of L-cysteine, free ACH levels in gastric juice decreased by a mean of 76% for 20 to 100min (p=0.0023, <0.0001, 0.0086, 0.0102 at 20-, 40-, 60and 100min, respectively). After placebo, peak ACH levels ranged from 11.5 to 52.7μM as compared to 1.5 to 20.2μM following L-cysteine. In gastric juice, the mean peak L-cysteine level was 11928μM at 40min and mean peak MTCA level 1824μM at 80min. At 80min after intake of L-cysteine MTCA level was 654-fold as compared with free ACH level in gastric juice. CONCLUSIONS: The first-pass metabolism of ethanol mediated by gastric mucosal cells and/or microbes results in a marked exposure of gastric mucosa to ACH. Without L-cysteine, ACH is distributed to local water phase and metabolized further to acetate by gastric mucosal low Km ALDH enzymes. As shown by high MTCA levels in gastric juice after ethanol and slow releasing L-cysteine, it can be calculated that up to 90 % of locally formed ACH is inactivated by Lcysteine, thus significantly reducing the exposure to carcinogenic acetaldehyde.