Different toxicological profile of two COMT inhibitors in vivo: the role of uncoupling effects.
The toxicity profiles of entacapone and tolcapone, novel catechol- O-methyl-transferase (COMT) inhibitors, have been reported to differ from each other. It has also been shown that tolcapone, but not entacapone, is a potent uncoupler of oxidative phosphorylation in vitroat low micromolar concentrations. Signs of hepatotoxicity induced by tolcapone treatment have been previously reported in toxicological studies and in clinical use. The present study was designed to investigate the mechanism of hepatotoxicity of tolcapone and its possible relationship to uncoupling of oxidative phosphorylation in vivo. A 15-day oral toxicity study with entacapone or tolcapone (300 and 500 mg/kg/day) was carried out, and 2, 4-dinitrophenol (DNP), a known uncoupling agent of oxidative phosphorylation, served as a positive reference substance (20 mg/kg/day). No treatment related findings were observed in entacapone-treated rats. Clinical chemistry parameters regarding hepatocellular damage were increased in tolcapone and DNP-treated animals. The energy status measured as ATP/ADP ratio from the liver samples and energy charge (EC) in liver cell mitochondria were diminished both in tolcapone- and in DNP-treated rats. These signs together with clinical symptoms consisting of increased respiration, decreased activity and drowsiness, and elevation of the rectal body temperature observed in tolcapone- and DNP-treated animals suggest a relationship between the treatment and uncoupling of oxidative phosphorylation in vivo.
Haasio
K
K
Orion Corporation, Orion Pharma, Espoo, Finland. kristiina.haasio@orionpharma.com
Nissinen
E
E
Sopanen
L
L
Heinonen
E H
EH
D000818:Animals; D001577:Benzophenones / Q000378:metabolism / Q000633:toxicity*; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols / Q000378:metabolism / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects; D009570:Nitriles; D009596:Nitrophenols; D010085:Oxidative Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077867:Tolcapone; D014475:Uncoupling Agents / Q000378:metabolism / Q000633:toxicity*
D001577:Benzophenones; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols; D004791:Enzyme Inhibitors; D009570:Nitriles; D009596:Nitrophenols; D014475:Uncoupling Agents; C071192:entacapone; D000077867:Tolcapone