Effects of nonsteroidal anti-inflammatory drugs on glutathione S-transferases of the rat digestive tract.
Nonsteroidal anti-inflammatory drugs (NSAIDs) have been demonstrated to reduce cancer rates in oesophagus, stomach and colon of humans and animals. Earlier, we showed that high human gastrointestinal tissue levels of glutathione S-transferase (GST), a family of detoxification enzymes consisting of class alpha, mu, pi and theta isoforms, were inversely correlated with cancer risk. We investigated whether the NSAIDs indomethacin, ibuprofen, piroxicam, acetyl salicylic acid (ASA), and sulindac, supplemented in the diet for 2 weeks at 25, 400, 400, 400, and 320 ppm, respectively, influenced gastrointestinal GSTs in male Wistar rats. In cytosolic fractions of oesophagus, stomach, intestine and liver, GST activity towards 1-chloro-2,4-dinitrobenzene was measured, GST isozyme levels were determined by densitometrical analysis of Western blots after immunodetection with monoclonal antibodies, and glutathione levels were determined by HPLC. GST activity and GST mu levels were increased (1.2-1.8 x) in oesophagus and small intestine by indomethacin, ibuprofen, piroxicam and sulindac. GST alpha levels were induced (1.2-2.8 x) in stomach by piroxicam, in small intestine by indomethacin, ibuprofen, piroxicam and sulindac, and in liver by piroxicam. GST pi levels were raised (1.9-3.6 x) in stomach by ibuprofen, ASA, and sulindac, and in small intestine by indomethacin, piroxicam, ASA, and sulindac. Glutathione levels were raised (1.2-2.3 x) by indomethacin and ASA in small intestine and by piroxicam in oesophagus. Enhancement of GSTs in the upper part of the digestive tract, resulting in a more efficient detoxification, may explain in part the anticarcinogenic properties of NSAIDs.
van Lieshout
E M
EM
Department of Gastroenterology, University Hospital St Radboud, Nijmegen, The Netherlands.
Tiemessen
D M
DM
Peters
W H
WH
Jansen
J B
JB
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology*; D016588:Anticarcinogenic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001241:Aspirin / Q000008:administration & dosage / Q000494:pharmacology; D003600:Cytosol / Q000201:enzymology; D004064:Digestive System / Q000187:drug effects* / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D004947:Esophagus / Q000187:drug effects / Q000201:enzymology; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000096:biosynthesis* / Q000235:genetics; D007052:Ibuprofen / Q000008:administration & dosage / Q000494:pharmacology; D007213:Indomethacin / Q000008:administration & dosage / Q000494:pharmacology; D007422:Intestines / Q000187:drug effects / Q000201:enzymology; D007527:Isoenzymes / Q000096:biosynthesis* / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D009928:Organ Specificity; D010894:Piroxicam / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013270:Stomach / Q000187:drug effects / Q000201:enzymology; D013379:Substrate Specificity; D013467:Sulindac / Q000008:administration & dosage / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016588:Anticarcinogenic Agents; D007527:Isoenzymes; D010894:Piroxicam; D013467:Sulindac; D005982:Glutathione Transferase; D005978:Glutathione; D001241:Aspirin; D007052:Ibuprofen; D007213:Indomethacin