Induction of gastric mucosal cell proliferation by the fungicide captan: role of tyrosine kinases.
Captan (1,2,3,6-tetrahydro-N-trichloromethylthiophthalmide), a widely used fungicide, has been shown to induce carcinoma in the gastrointestinal tract of rodents. However, little is known about the captan induction of early biochemical changes in the gastrointestinal tract. The present investigation examines the changes in gastric mucosal proliferative activity in 2-month-old Fischer 344 rats following a daily injection (s.c.) of captan (100 mg/kg body wt.) in DMSO while being infused (osmotic minipump) with the same compound (7.14 mg captan/kg body wt./h) for 2 weeks. The control rats received the vehicle the same way. The change in proliferative activity was related to tyrosine kinase (Tyr-k) activity and tyrosine-specific phosphorylation of protein(s) in gastric mucosal membranes since these intracellular events are thought to play an important role in proliferation, differentiation and transformation of cells. After 2 weeks of captan administration gastric mucosal DNA synthesis and thymidine kinase activity (indicators of proliferative activity) were increased by 330% (P less than 0.025) and 98% (P less than 0.025), respectively, when compared with the corresponding controls. Gastric mucosal DNA content was also increased by 90% (P less than 0.025) after administration of captan. These increases were associated with about 3-fold rise in Tyr-k activity and 2-fold increase in tyrosine phosphorylation of 6 mucosal membrane proteins with Mr of 105, 90, 60, 55, 48 and 37 kDa. We conclude that captan stimulates gastric mucosal cell proliferation, and activation of Tyr-k and tyrosine phosphorylation of certain membrane proteins may be important in the regulation of this process.
Wahby
M
M
Research Service, Veterans Administration Medical Center, Allen Park, MI 48101.
Shelef
L A
LA
Luk
G D
GD
Majumdar
A P
AP
D000818:Animals; D002215:Captan / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis; D005753:Gastric Mucosa / Q000187:drug effects* / Q000201:enzymology; D007260:Infusion Pumps; D007279:Injections, Subcutaneous; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D013937:Thymidine Kinase / Q000378:metabolism*
D008565:Membrane Proteins; D004247:DNA; D013937:Thymidine Kinase; D011505:Protein-Tyrosine Kinases; D002215:Captan