THE EFFECT OF NAPROXEN ON GENES ASSOCIATED WITH DNA DAMAGE AND REPAIR IN THE STOMACH OF HEALTHY VOLUNTEERES BY MICROARRAY ANALYSIS.

Introduction: Microarray analysis provides the opportunity to study large numbers of drug—gene interactions. Here we report some of the effects of the non steroidal anti-inflammatory drug (NSAID) naproxen on the transcription of genes in the human gastric mucosa. Methods: Four (2m, 2f) healthy volunteers received naproxen 500 mg twice daily, for 2 days. Four control subjects (2m, 2f) received no active drug. Antral biopsies (4) were taken by endoscopy before and following (3, 12, and 48 h) treatment. Total RNA was extracted from 2 of the biopsies with RNeasy® mini kits and 2 were used for histology. The expression of -8000 genes were assessed by cDNA microarray. After normalisation the expression of 1258 genes were significanty altered by naproxen as judged by ANOVA (p < 0.05). Data in brackets are maximum percent increase compared to control. Results: Scrutiny of the microarray data identified increased transcription of genes coding for the following proteins at 3 h: caspase 1 (29%) and (21%), E2F dimmerization partner 2 (18%); at 12 h: caspase 3 (35%) poly (ADP-ribose) synthase (33%), NFkB (14.5%), methyl GpG binding domain protein 4 (33%), APC (20κ), DNA protein kinase (43%) damage specific DNA binding protein 2 (24%), cell division cycle 25A (17%), checkpoint kinase 2 (47%, cyclin dependent kinase (CDK) 6 (20%), cydin H (33%); and at 48 h: caspase 9 (31%), xeroderma pigmentosa group A (22%), mothers against decapentaplegic homologue 6 (30%), CDK 7(40%), CDK associated protein 1 (37%). Histological assessment found no inflammatory changes in the gastric mucosa correlated to drug treatment. Conclusion: These transcriptional changes suggest naproxen not only causes apoptosis but also DNA double-strand breaks, stimulates DNA repair responses and checkpoint cell cycle arrest. This preliminary analysis of an in vivo human experiment is consistent with the in vitro findings of others. The data also allow identification of previously unrecognised... [ABSTRACT FROM AUTHOR]