Effect of indomethacin, aspirin, nordihydroguairetic acid, and piperonyl butoxide on cyclophosphamide-induced bladder damage.
Cyclophosphamide (CP), a widely used antineoplastic and immunosuppressant drug, is a prototypical bladder toxin in humans and experimental animals. CP itself is biologically inert. However, following bioactivation, acrolein, a potent tissue alkylator is generated. It is currently accepted that CP activation occurs via oxidative metabolism by the mixed-function oxidase system (MFO). Previous evidence from this laboratory demonstrated that CP can be metabolized by pathways other than MFO. In the current study, it was demonstrated that two inhibitors of the prostaglandin hydroperoxide synthase enzyme system, indomethacin and nordihydroguairetic acid (NDGA), diminish CP-induced bladder toxicity. However, the ability of these inhibitors to provide protection did not appear to be due to interference with CP metabolism. Many of the biologic effects of acrolein have been attributed to interaction with cellular thiols. Indomethacin and NDGA protected against CP-induced losses of soluble thiols in liver and protein thiols in bladder. Additionally, animals pretreated with indomethacin prior to CP appeared to have more glutathione available for conjugation, providing a potential mechanism for its protective effects against CP-induced bladder damage.
Frasier
L
L
Department of Pharmacology and Toxicology, College of Pharmacy, University of Texas, Austin 78712.
Kehrer
J P
JP
D000171:Acrolein / Q000652:urine; D000818:Animals; D001241:Aspirin / Q000494:pharmacology*; D003520:Cyclophosphamide / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects; D005978:Glutathione / Q000187:drug effects; D006454:Hemoglobins / Q000378:metabolism; D007213:Indomethacin / Q000494:pharmacology*; D008297:Male; D009637:Masoprocol / Q000494:pharmacology*; D051379:Mice; D008813:Mice, Inbred ICR; D006899:Mixed Function Oxygenases / Q000187:drug effects; D010539:Permeability / Q000187:drug effects; D010882:Piperonyl Butoxide / Q000494:pharmacology*; D011506:Proteins / Q000187:drug effects; D012995:Solubility; D013438:Sulfhydryl Compounds / Q000378:metabolism; D001743:Urinary Bladder / Q000737:chemistry / Q000187:drug effects*; D001745:Urinary Bladder Diseases / Q000097:blood / Q000139:chemically induced / Q000517:prevention & control
D006454:Hemoglobins; D011506:Proteins; D013438:Sulfhydryl Compounds; D000171:Acrolein; D009637:Masoprocol; D003520:Cyclophosphamide; D004247:DNA; D006899:Mixed Function Oxygenases; D005978:Glutathione; D010882:Piperonyl Butoxide; D001241:Aspirin; D007213:Indomethacin