Skip to main content
Log in

Different toxicological profile of two COMT inhibitors in vivo: the role of uncoupling effects

  • Published:
Journal of Neural Transmission Aims and scope Submit manuscript

Summary.

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 vitro at 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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Author information

Authors and Affiliations

Authors

Additional information

Received January 24, 2002; accepted March 18, 2002 Published online June 28, 2002

Acknowledgements The authors thank Mr. P. Hakulinen for statistical analysis and Ms. M. Heikkilä and Mr. T. Korkolainen for plasma and liver concentration analysis.

Authors' address: K. Haasio, D.V.M., Orion Pharma, Research, P.O. Box 65, FIN-02101 Espoo, Finland, e-mail: kristiina.haasio@orionpharma.com

Rights and permissions

Reprints and permissions

About this article

Cite this article

Haasio, K., Nissinen, E., Sopanen, L. et al. Different toxicological profile of two COMT inhibitors in vivo: the role of uncoupling effects. J Neural Transm 109, 1391–1401 (2002). https://doi.org/10.1007/s00702-002-0748-x

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00702-002-0748-x

Navigation