Studies on the tight-binding nature of tolcapone inhibition of soluble and membrane-bound rat brain catechol-O-methyltransferase

• Type: Article in International Scientific Journal
• Date: 1997

Authors

Borges, Nuno (Author) FCNAUP; vieira-coelho, ma (Author) Other; Parada, A (Author) Other; soares-da-silva, p (Author) FMUP

Journal

Title: Journal of Pharmacology and Experimental Therapeutics

Vol. 282

Pages: 812-817

ISSN: 0022-3565

Publisher: American Society for Pharmacology and Experimental Therapeutics

Indexing

ISI Web of Knowledge - 37 Citations

Scopus - 34 Citations

Other information

Authenticus ID: P-001-AZF

Abstract (EN): Catechol-O-methyltransferase (COMT) is an enzyme that plays an important role in the inactivation of catecholamine neurotransmitters. Experimental and clinical data suggest that COMT inhibitors may be useful in Parkinsonian patients. Among COMT inhibitors, nitrocatechol derivatives are the most potent and selective. In this study, we evaluated the kinetics of rat brain COMT, as well as its mechanisms of inhibition by tolcapone, Rat whole-brain homogenates and the corresponding soluble and membrane-bound fractions were evaluated for their epinephrine 3-O-methylating activity. Tolcapone exhibited a very low IC50 in all the three enzyme preparations. In whole-brain homogenates, saturation curves made in the presence of 1 nM tolcapone displayed, when compared with controls, a reduction in V-max without changes in K-m, which suggested a noncompetitive type of inhibition, This was confirmed by experiments in which the IC50, value for tolcapone was not affected by substrate concentration. Nevertheless, this classic kinetic analysis is not suitable for a tight-binding inhibitor. A very low IC50, an inhibition potency that is dependent on the previous contact time of the inhibitor with the enzyme and an enzyme titrating capacity were the three criteria that tolcapone met as a tight-binding inhibitor in the rat brain. In conclusion, our results show that tolcapone is a highly potent tight-binding inhibitor of brain soluble and membrane-bound COMT, but because of difficulties in determining the type of inhibition for this type of compound, we cannot confirm previous claims about the competitive type of COMT inhibition produced by tolcapone.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 6