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Lack of increased oxidative stress in catechol-O-methyltransferase (COMT)-deficient mice

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Abstract

The effect of catechol-O-methyltransferase (COMT) deficiency on methamphetamine-induced hydroxyl radical production in the brain was assessed by the salicylate trapping method. Methamphetamine-induced hyperthermia was also studied. Furthermore, the effect of COMT deficiency on the activities of glutathione S-transferase, quinone reductase and liver mono-oxygenases was assessed with and without l-dopa challenge. Finally, two alternative pathways of l-dopa metabolism were evaluated. Methamphetamine increased 2,3-dihydroxybenzoic acid levels only slightly (n.s.) at the lowest dose level (2.5 mg/kg × 4 i.p.). This was accompanied by a simultaneous increase in salicylate levels so that the 2,3-dihydroxybenzoic acid/salicylate ratio decreased correspondingly. Most importantly, no COMT genotype-dependent changes were observed. However, hyperthermia was induced even at the lowest methamphetamine dose, the COMT-deficient mice being most sensitive. COMT deficiency did not significantly change the activities of liver glutathione S-transferase, quinone reductase or 7-ethoxyresorufin and 7-pentoxyresorufin O-dealkylation. In COMT-deficient female mice, l-dopa (30–80 mg/kg b.i.d. for 2 days) did not induce any significant changes in liver or brain glutathione S-transferase and quinone reductase activity or liver 7-ethoxyresorufin O-deethylation activity. The levels of l-dopa conjugates in urine were also negligible in COMT-deficient mice. Skin tyrosinase activity was increased in 7- to 8-day-old hairless COMT-deficient pups. The present results suggest that despite the increased hyperthermic response, COMT deficiency does not increase methamphetamine-induced hydroxyl radical production or change significantly the activity of certain enzymes involved in defense against reactive oxygen species. In conclusion, we found no evidence of increased oxidative stress in the liver or brain of adult mice lacking COMT activity.

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Acknowledgements

The authors wish to thank Dr Ewen MacDonald for revision of the manuscript. We also appreciate the excellent technical assistance of Mrs Jaana Leskinen and Ms Terttu Jokinen. This work was supported in part by grants from the Finnish Cultural Foundation of Northern Savo, the Finnish Parkinson Foundation, the Association of Finnish Pharmacies and the Finnish Pharmacists’ Association (to M.M.F.) and the Academy of Finland (to P.T.M., no. 50324).

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, University of Kuopio, PO Box 1627, 70211, Kuopio, Finland

    Markus M. Forsberg, Risto O. Juvonen, Petra Helisalmi & Pekka T. Männistö

  2. Department of Pharmaceutical Chemistry, University of Kuopio, PO Box 1627, 70211, Kuopio, Finland

    Jukka Leppänen

  3. Department of Physiology and Cellular Biophysics and Center for Neurobiology and Behavior, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY 10032, USA

    Joseph A. Gogos

  4. Laboratory of Human Neurogenetics, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA

    Maria Karayiorgou

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  1. Markus M. Forsberg
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Correspondence to Markus M. Forsberg.

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Forsberg, M.M., Juvonen, R.O., Helisalmi, P. et al. Lack of increased oxidative stress in catechol-O-methyltransferase (COMT)-deficient mice. Naunyn-Schmiedeberg's Arch Pharmacol 370, 279–289 (2004). https://doi.org/10.1007/s00210-004-0967-9

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