Entacapone does not induce conformational changes in liver mitochondria or skeletal muscle in vivo.
Entacapone and tolcapone, novel catechol-O-methyl-transferase (COMT) inhibitors, have been developed for the treatment of Parkinson's disease in combination with levodopa. Three fatal cases of drug-induced hepatitis, one with hepatic necrosis and mitochondrial changes have been reported in clinical use of tolcapone. In vitro tolcapone has been shown to induce uncoupling of oxidative phosphorylation. Liver and skeletal muscle tissues from an oral rat toxicity study were used to investigate the influence of entacapone, tolcapone (300 and 500 mg/kg/day) or a known uncoupling agent, 2,4-dinitrophenol (DNP), (20 mg/kg/ day) on the cell morphology. Centrolobular hypertrophy was revealed in the histopathology of the liver in tolcapone-treated rats. Transmission electron microscopy (TEM) of the liver and skeletal muscle tissue, revealed mitochondrial swelling and reduced matrix density with deformation of cristae in the tolcapone and DNP groups. Intermyofibrillar edema was characteristic of the skeletal muscle tissue of DNP- and tolcapone-exposed animals. In the tolcapone group, also the sarcomeres were prominent. Treatment-related light microscopic or TEM findings were not observed either in entacapone-treated or control animals. The similarity of structural damages induced by both tolcapone- and DNP suggests that uncoupling of oxidative phosphorylation may contribute to the toxicity of tolcapone in the rat.
Haasio
Kristina
K
Orion Corporation, Orion Pharma, Espoo, Finland. kristiina.haasio@orionpharma.com
Lounatmaa
Kari
K
Sukura
Antti
A
D019297:2,4-Dinitrophenol / Q000008:administration & dosage / Q000633:toxicity; D000284:Administration, Oral; D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000633:toxicity*; D001577:Benzophenones / Q000008:administration & dosage / Q000633:toxicity; D002396:Catechols / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000139:chemically induced / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000648:ultrastructure; D008933:Mitochondrial Swelling / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000473:pathology; D009210:Myofibrils / Q000187:drug effects / Q000648:ultrastructure; D009570:Nitriles; D009596:Nitrophenols; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077867:Tolcapone; D018675:Toxicity Tests; D014475:Uncoupling Agents / Q000008:administration & dosage / Q000633:toxicity
D000978:Antiparkinson Agents; D001577:Benzophenones; D002396:Catechols; D009570:Nitriles; D009596:Nitrophenols; D014475:Uncoupling Agents; C071192:entacapone; D000077867:Tolcapone; D019297:2,4-Dinitrophenol