The catechol-O-methyltransferase inhibitors tolcapone and entacapone uncouple and inhibit the mitochondrial respiratory chain in HepaRG cells

Toxicology in Vitro : an International Journal Published in Association with BIBRA
David GrünigStephan Krähenbühl

Abstract

The catechol-O-methyltransferase inhibitor tolcapone causes hepatotoxicity and mitochondrial damage in animal models. We studied the interaction of tolcapone with mitochondrial respiration in comparison to entacapone in different experimental models. In HepaRG cells (human cell-line), tolcapone decreased the ATP content (estimated IC50100±15μM) and was cytotoxic (estimated IC50333±45μM), whereas entacapone caused no cytotoxicity and no ATP depletion up to 200μM. Cytochrome P450 induction did not increase the toxicity of the compounds. In HepaRG cells, tolcapone (not entacapone) inhibited maximal complex I- and complex II-linked oxygen consumption. In intact mouse liver mitochondria, tolcapone stimulated state 2 complex II-linked respiration and both compounds inhibited state 3 respiration of complex IV. Mitochondrial uncoupling was confirmed for both compounds by stimulation of complex I-linked respiration in the presence of oligomycin. Inhibition of complex I, II and IV for tolcapone and of complex I and IV for entacapone was directly demonstrated in disrupted mouse liver mitochondria. In HepaRG cells, tolcapone-induced inhibition of mitochondrial respiration was associated with increased lactate and ROS production and hepatoc...Continue Reading

References

Jul 1, 1971·Clinica Chimica Acta; International Journal of Clinical Chemistry·C Olsen
Jul 1, 1980·Physiological Reviews·S G McLaughlin, J P Dilger
Oct 31, 1994·Clinica Chimica Acta; International Journal of Clinical Chemistry·S KrähenbühlC L Hoppel
Sep 30, 1998·Lancet·F AssalL Rubbici-Brandt
Dec 3, 1999·British Journal of Clinical Pharmacology·K JorgaR Gasser
Feb 19, 2000·Archives of Neurology·C W Olanow
Oct 29, 2000·Digestive Diseases and Sciences·L SpahrA Hadengue
Mar 23, 2001·Journal of Neural Transmission·K HaasioE H Heinonen
Oct 24, 2002·European Journal of Pharmacology·Kristiina HaasioErkki Nissinen
Nov 28, 2002·Journal of Neural Transmission·K HaasioE H Heinonen
Feb 18, 2003·Chemical Research in Toxicology·Kirsten S SmithTimothy L Macdonald
Aug 12, 2003·Drug Safety : an International Journal of Medical Toxicology and Drug Experience·Nuno Borges
Mar 1, 2005·Cell·Robert S BalabanToren Finkel
Mar 31, 2005·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Priska KaufmannStephan Krähenbühl
Jan 24, 2007·Chemico-biological Interactions·André GuillouzoChristiane Guguen-Guillouzo
Oct 3, 2007·Clinical Neuropharmacology·Mark F Lew, Greg Kricorian
Sep 29, 2009·Toxicological Sciences : an Official Journal of the Society of Toxicology·Jenny J FischerHubert Koester
Dec 19, 2009·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Sébastien AnthérieuAndré Guillouzo
Nov 3, 2010·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Joanna D StewartPatrick F Chinnery
Nov 26, 2010·International Review of Neurobiology·Kristiina Haasio
Nov 9, 2012·Toxicological Sciences : an Official Journal of the Society of Toxicology·Andrea FelserStephan Krähenbühl
Dec 12, 2012·Toxicologic Pathology·Gerald W Dorn
Mar 10, 2015·Toxicology in Vitro : an International Journal Published in Association with BIBRA·Laleh KamalianB Kevin Park
Mar 15, 2015·Biochimica Et Biophysica Acta·François SinghJoffrey Zoll
Dec 6, 2016·Frontiers in Pharmacology·Benjamin BergerManuel Haschke

❮ Previous
Next ❯

Citations

Apr 25, 2018·Toxicological Sciences : an Official Journal of the Society of Toxicology·David GrünigStephan Krähenbühl
Jan 30, 2018·Experimental and Therapeutic Medicine·Pei-Lan ZhangChen-Hua Li
Nov 2, 2017·Translational Neurodegeneration·Panchanan MaitiGary L Dunbar
Dec 19, 2020·Clinical Pharmacology and Therapeutics·Fabio BachmannStephan Krähenbühl
Mar 9, 2021·Bioorganic & Medicinal Chemistry Letters·Junichiro UdaTakashi Iwanaga
Jul 21, 2020·Drug Discovery Today·Tiago Barros SilvaPatrício Soares-da-Silva
Sep 8, 2021·Frontiers in Pharmacology·Huan YangJoost B Beltman
Aug 3, 2021·Antimicrobial Agents and Chemotherapy·Bridgette M CummingAdrie J C Steyn

❮ Previous
Next ❯

Related Concepts

Related Feeds

Aphasia

Aphasia affects the ability to process language, including formulation and comprehension of language and speech, as well as the ability to read or write. Here is the latest research on aphasia.