Importance of membrane-bound catechol-O-methyltransferase in L-DOPA metabolism: a pharmacokinetic study in two types of Comt gene modified mice.

British Journal of Pharmacology
M KäenmäkiP T Männistö

Abstract

Catechol-O-methyltransferase (COMT) metabolizes compounds containing catechol structures and has two forms: soluble (S-COMT) and membrane-bound (MB-COMT). Here we report the generation of a mouse line that expresses MB-COMT but not S-COMT. We compared the effects of deleting S-COMT only or both COMT forms on the pharmacokinetics of oral L-DOPA. L-DOPA (10 mg kg(-1)) and carbidopa (30 mg kg(-1)) were given to mice by gastric tube, and samples were taken at various times. HPLC was used to measure L-DOPA in plasma and tissue samples, and dopamine and its metabolites in brain. Immunohistochemistry and Western blotting were used to characterize the distribution of COMT protein isoforms. Lack of S-COMT did not affect the levels of L-DOPA in plasma or peripheral tissues, whereas in the full COMT-knock-out mice, these levels were increased. The levels of 3-O-methyldopa were significantly decreased in the S-COMT-deficient mice. In the brain, L-DOPA levels were not significantly increased, and dopamine was increased only in females. The total COMT activity in the S-COMT-deficient mice was 22-47% of that in the wild-type mice. In peripheral tissues, female mice had lower COMT activity than the males. In S-COMT-deficient mice, MB-COMT in t...Continue Reading

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Citations

Jul 10, 2010·Psychopharmacology·Anne TammimäkiPekka T Männistö
Oct 27, 2010·Pharmacogenetics and Genomics·Anne Emilia Tammimäki, Pekka T Männistö
Aug 20, 2011·Basic & Clinical Pharmacology & Toxicology·Nadia SchendzielorzAtso Raasmaja
Mar 27, 2012·Neurogastroenterology and Motility : the Official Journal of the European Gastrointestinal Motility Society·L WangY Taché
Jul 9, 2016·Progress in Neurobiology·Philippe De DeurwaerdèreMark J Millan
Apr 5, 2017·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Anne TammimäkiPekka T Männistö
Dec 1, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Monique HoonAnél Petzer
Mar 16, 2013·Journal of Separation Science·Fátima Milhano SantosLuís António Passarinha
Aug 29, 2017·Biochemical Pharmacology·Svetlana SemenovaPertti Panula

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