A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
Importance of membrane-bound catechol-O-methyltransferase in L-DOPA metabolism: a pharmacokinetic study in two types of Comt gene modified mice
Tekijät: Kaenmaki M, Tammimaki A, Garcia-Horsman JA, Myohanen T, Schendzielorz N, Karayiorgou M, Gogos JA, Mannisto PT
Kustantaja: WILEY-BLACKWELL
Julkaisuvuosi: 2009
Journal: British Journal of Pharmacology
Tietokannassa oleva lehden nimi: BRITISH JOURNAL OF PHARMACOLOGY
Lehden akronyymi: BRIT J PHARMACOL
Vuosikerta: 158
Numero: 8
Aloitussivu: 1884
Lopetussivu: 1894
Sivujen määrä: 11
ISSN: 0007-1188
DOI: https://doi.org/10.1111/j.1476-5381.2009.00494.x
Tiivistelmä
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 center dot kg-1) and carbidopa (30 mg center dot 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.
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 center dot kg-1) and carbidopa (30 mg center dot 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.
Turun yliopiston Tutkimustietojärjestelmän portaali