Delayed O-methylation of l-DOPA in MB-COMT-deficient mice after oral administration of l-DOPA and carbidopa

Abstract

1. Catechol-O-methyltransferase (COMT) is involved in the O-methylation of l-DOPA, dopamine, and other catechols. The enzyme is expressed in two isoforms: soluble (S-COMT), which resides in the cytoplasm, and membrane-bound (MB-COMT), which is anchored to intracellular membranes.

2. To obtain specific information on the functions of COMT isoforms, we studied how a complete MB-COMT deficiency affects the total COMT activity in the body, peripheral l-DOPA levels, and metabolism after l-DOPA (10 mg kg⁻¹) plus carbidopa (30 mg kg⁻¹) administration by gastric tube in wild-type (WT) and MB-COMT-deficient mice. l-DOPA and 3-O-methyl-l-DOPA (3-OMD) levels were assayed in plasma, duodenum, and liver.

3. We showed that the selective lack of MB-COMT did not alter the total COMT activity, COMT enzyme kinetics, l-DOPA levels, or the total O-methylation of l-DOPA but delayed production of 3-OMD in plasma and peripheral tissues.

Keywords:

• COMT isoforms
• knock-in mutation
• l-DOPA
• MB-COMT
• metabolism
• mouse pharmacokinetics
• S-COMT
• site-directed mutation

Acknowledgments

The authors warmly thank Liisa Lappalainen M.Sc. and Ms. Kati Rautio for their excellent technical assistance.

Declaration of interest

The authors report no conflict of interest. The authors alone are responsible for the content and writing of the article. This work was supported by Academy of Finland (AT grant number 1257339, PTM grant number 257898) and Sigrid Juselius Foundation (PTM).