Troglitazone acts by PPARgamma and PPARgamma-independent pathways on LLC-PK1-F+ acid-base metabolism.
Troglitazone was studied in pH-sensitive LLC-PK1-F+ cells to determine the effect on pHi and glutamine metabolism as well as the role of peroxisome proliferator-activated receptor (PPARgamma)-dependent and PPARgamma-independent signaling pathways. Troglitazone induces a dose-dependent cellular acidosis that occurs within 4 min and persists over 18 h as a result of inhibiting Na+/H+ exchanger-mediated acid extrusion. Cellular acidosis was associated with glutamine-dependent augmented [15N]ammonium production and decreased [15N]alanine formation from 15N-labeled glutamine. The shift in glutamine metabolism from alanine to ammoniagenesis appears within 3 h and is associated after 18 h with both a reduction in assayable alanine aminotransferase (ALT) activity as well as cellular acidosis. The relative contribution of troglitazone-induced cellular acidosis vs. the decrease in assayable ALT activity to alanine production could be demonstrated. The PPARgamma antagonist bisphenol A diglycide ether (BADGE) reversed both the troglitazone-induced cellular acidosis and ammoniagenesis but enhanced the troglitazone reduction of assayable ALT activity; BADGE also blocked troglitazone induction of peroxisome proliferator response element-driven firefly luciferase activity. The protein kinase C (PKC) inhibitor chelerythrine mimics troglitazone effects, whereas phorbol ester reverses the effects on ammoniagenesis consistent with troglitazone negatively regulating the DAG/PKC/ERK pathway. Although functional PPARgamma signaling occurs in this cell line, the major troglitazone-induced acid-base responses appear to be mediated by pathway(s) involving PKC/ERK.
D000136:Acid-Base Equilibrium / Q000187:drug effects* / Q000502:physiology; D000138:Acidosis / Q000139:chemically induced; D000409:Alanine / Q000378:metabolism; D000470:Alkaloids; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001559:Benzhydryl Compounds; D053119:Benzophenanthridines; D002273:Carcinogens / Q000494:pharmacology; D002839:Chromans / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004852:Epoxy Compounds / Q000494:pharmacology; D017930:Genes, Reporter; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D018374:LLC-PK1 Cells; D010617:Phenanthridines / Q000494:pharmacology; D010957:Plasmids; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D000644:Quaternary Ammonium Compounds / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013552:Swine; D045162:Thiazolidinediones / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism*; D000077288:Troglitazone; D000098826:Bisphenol A Compounds
D000409:Alanine; D000470:Alkaloids; D000970:Antineoplastic Agents; D001559:Benzhydryl Compounds; D053119:Benzophenanthridines; D002273:Carcinogens; D002839:Chromans; D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D010617:Phenanthridines; D011493:Protein Kinase C; D000644:Quaternary Ammonium Compounds; D018160:Receptors, Cytoplasmic and Nuclear; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077288:Troglitazone; C016299:chelerythrine; C019273:bisphenol A diglycidyl ether; D000098826:Bisphenol A Compounds