title: Activation of Fas receptor modulates cytochrome P450 3A4 expression in human colon carcinoma cells.
abstract: The Fas (CD95, APO-1) receptor is a transmembrane cell surface receptor that mediates apoptosis in many cell types when bound by the Fas ligand or cross-linked by agonistic anti-Fas antibodies. Fas activation engages a potent and rapid signaling mechanism in a variety of cell types. In the present study, we have investigated the effects of Fas receptor activation on CYP3A4 expression in human colon carcinoma HT-29 cells. The intracellular ceramide levels were significantly enhanced by the treatment with the anti-Fas antibodies and both CYP3A4 protein and mRNA expression was suppressed by Fas activation in a dose-dependent manner. Immunoblot analyses showed that the expression of iNOS protein was significantly stimulated by an anti-Fas antibody treatment in HT-29 cells. Fas receptor activation also increased the generation of reactive oxygen species, and N-acetylcysteine, a well-known antioxidant, could block Fas-mediated iNOS induction. These results show that the Fas receptor-mediated signaling pathways modulate CYP3A4 expression in human colon cancer cells. Overall, iNOS induction and P450 3A4 suppression by Fas activation may cause toxic cellular damage in gastrointestinal tissues.
authors: College of Pharmacy, Chung-Ang University, 221 Huksuk-Dong, Dongjak-Ku, Seoul 156-756, South Korea. yjchun@cau.ac.kr
authors: Young-Jin
authors: YJ
authors: Chun
authors: Sungsik
authors: S
authors: Park
authors: Soon Ae
authors: SA
authors: Yang
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002518:Ceramides / Q000096:biosynthesis; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D019073:HT29 Cells; D006801:Humans; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger / Q000096:biosynthesis; D017382:Reactive Oxygen Species / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D002518:Ceramides; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D019014:fas Receptor; D003577:Cytochrome P-450 Enzyme System; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human