Chemotherapy induced gastrointestinal toxicity in rats: involvement of mitochondrial DNA, gastrointestinal permeability and cyclooxygenase -2.
OBJECTIVE
The gastrointestinal damage induced by xenobiotics is occurring more frequently and with greater toxicological significance than previously thought. Although there are some preliminary clinical studies and reports, there does not appear to be an extensive examination of gastrointestinal toxicity of various chemotherapeutic agents in the rat. This study was undertaken to examine the suitability of a rat model to detect the gastrointestinal damage after administration of various anti-neoplastic agents including etoposide, teniposide, melphalan, 5-fluorouracil, methotrexate and cisplatin.


METHODS
Acute toxic doses of indomethacin and chemotherapeutic agents were administered to rats. The urinary excretion of orally administered sucrose and 51(Cr)-EDTA were measured as markers of gastroduodenal and intestinal permeability, respectively. Cyclooxygenase-2 messenger RNA and mitochondrial DNA damage were measured as toxicological endpoints.


RESULTS
Each anti-neoplastic agent examined induced appreciable and significant dose-dependent increase in gastrointestinal permeability that correlated with gross toxicological and pathological changes to the gastrointestinal tract including ulceration and bleeding. COX-2 mRNA was upregulated > 2 fold in intestinal mucosa with enteropathy and dose-dependent mitochondrial oxidative damage was apparent in gastric and intestinal mucosa. After administration of each drug, the rats presented with histological evidence of drug-induced gastroenteropathy, ulceration and increased cecal hemoglobin.


CONCLUSIONS
The rat appears to be a suitable model to study gastrointestinal toxicity of chemotherapeutic agents and non-steroidal anti-inflammatory drugs. Damage to mitochondrial DNA occurs in both the gastric and intestinal epithelium after the administration of these agents and may be an important factor in the pathogenesis and resolution of gastrointestinal toxicity.
Yáñez
Jaime A
JA
Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Pullman, Washington 99164-6534, USA.
Teng
Xiao Wei
XW
Roupe
Kathryn A
KA
Fariss
Marc W
MW
Davies
Neal M
NM
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity; D000970:Antineoplastic Agents / Q000633:toxicity; D002463:Cell Membrane Permeability / Q000502:physiology; D051546:Cyclooxygenase 2; D004272:DNA, Mitochondrial / Q000502:physiology*; D004195:Disease Models, Animal; D005767:Gastrointestinal Diseases / Q000139:chemically induced* / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D007213:Indomethacin / Q000633:toxicity*; D007527:Isoenzymes / Q000235:genetics / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D004272:DNA, Mitochondrial; D007527:Isoenzymes; D008565:Membrane Proteins; D012333:RNA, Messenger; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D007213:Indomethacin