Organophosphorus compound-induced modification of SH-SY5Y human neuroblastoma mitochondrial transmembrane potential.
Organophosphorus (OP) compounds inhibit mitochondrial enzymes, respiration, and ATP generation, in addition to inducing structural changes such as matrix swelling. This implicates mitochondria as primary subcellular targets for these compounds. In this study, the health and function of cellular mitochondria following OP compound exposure were assessed by evaluating the mitochondrial transmembrane potential (DeltaPsi(m)). This was done by measuring the changes in DeltaPsi(m) in SH-SY5Y human neuroblastoma cells incubated with the cationic fluorochrome, rhodamine 123 (5 microg/ml), and the OP compounds tri-ortho-tolyl phosphate (TOTP), triphenyl phosphite (TPPi), or parathion for 7.5 to 960 minutes. OP compounds (100 microM to 1 mM) induced significant concentration-dependent mitochondrial hyperpolarization with peak maxima occurring at 60 (TOTP, TPPi) or 120 (parathion) min. Following this, the mitochondrial membranes gradually depolarized. Pretreatment with cyclosporin A (500 nM, 30 h), a mitochondrial permeability transition pore (PTP) inhibitor, decreased the hyperpolarization. In contrast, 30-h pretreatment with the muscarinic receptor agonist carbachol (1 mM) significantly increased DeltaPsi(m) and delayed subsequent depolarization. Hyperpolarization and subsequent depolarization of mitochondrial membranes occurred 16 to 24 h prior to a loss of substrate adhesion or an increase in DNA fragmentation, indicating that mitochondria were a primary target in OP compound-initiated cytotoxicity.
Carlson
K
K
Virginia-Maryland Regional College of Veterinary Medicine, Blacksburg, Virginia 24061, USA.
Ehrich
M
M
D053938:DNA Fragmentation / Q000187:drug effects; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D009447:Neuroblastoma / Q000473:pathology; D009943:Organophosphorus Compounds / Q000633:toxicity*; D014407:Tumor Cells, Cultured
D009943:Organophosphorus Compounds