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Importance of membrane‐bound catechol‐O‐methyltransferase in L‐DOPA metabolism: a pharmacokinetic study in two types of Comt gene modified mice
Author(s) -
Käenmäki M,
Tammimäki A,
GarciaHorsman JA,
Myöhänen T,
Schendzielorz N,
Karayiorgou M,
Gogos JA,
Männistö PT
Publication year - 2009
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2009.00494.x
Subject(s) - catechol o methyl transferase , endocrinology , carbidopa , medicine , dopamine , metabolite , pharmacokinetics , isozyme , chemistry , levodopa , pharmacology , biology , biochemistry , genotype , enzyme , gene , parkinson's disease , disease
Background and purpose: 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. Experimental approach: 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. Key results: 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. Conclusions and implications: In S‐COMT‐deficient mice, MB‐COMT in the liver and the duodenum is able to O‐methylate about one‐half of exogenous L‐DOPA. Sexual dimorphism and activity of the two COMT isoforms seems to be tissue specific and more prominent in peripheral tissues than in the brain.