Human CYP2D6 in the Brain Is Protective Against Harmine-Induced Neurotoxicity: Evidence from Humanized CYP2D6 Transgenic
- PDF / 1,945,295 Bytes
- 14 Pages / 595.276 x 790.866 pts Page_size
- 11 Downloads / 152 Views
ORIGINAL ARTICLE
Human CYP2D6 in the Brain Is Protective Against Harmine-Induced Neurotoxicity: Evidence from Humanized CYP2D6 Transgenic Mice Marlaina R. Stocco 1,2 Rachel F. Tyndale 1,2,4
&
Cole Tolledo 1,2
&
Fariba Baghai Wadji 2
&
Frank J. Gonzalez 3
&
Sharon Miksys 1,2
&
Received: 26 May 2020 / Accepted: 28 July 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract CYP2D6 metabolically inactivates several neurotoxins, including beta-carbolines, which are implicated in neurodegenerative diseases. Variation in CYP2D6 within the brain may alter local inactivation of neurotoxic beta-carbolines, thereby influencing neurotoxicity. The beta-carboline harmine, which induces hypothermia and tremor, is metabolized by CYP2D6 to the nonhypothermic/non-tremorgenic harmol. Transgenic mice (TG), expressing human CYP2D6 in addition to their endogenous mouse CYP2D, experience less harmine-induced hypothermia and tremor compared with wild-type mice (WT). We first sought to elucidate the role of CYP2D in general within the brain in harmine-induced hypothermia and tremor severity. A 4-h intracerebroventricular (ICV) pretreatment with the CYP2D inhibitor propranolol increased harmine-induced hypothermia and tremor in TG and increased harmine-induced hypothermia in WT. We next sought to specifically demonstrate that human CYP2D6 expressed in TG brain altered harmine response severity. A 24-h ICV propranolol pretreatment, which selectively and irreversibly inhibits human CYP2D6 in TG brain, increased harmine-induced hypothermia. This 24-h pretreatment had no impact on harmine response in WT, as propranolol is not an irreversible inhibitor of mouse CYP2D in the brain, thus confirming no offtarget effects of ICV propranolol pretreatment. Human CYP2D6 activity in TG brain was sufficient in vivo to mitigate harmineinduced neurotoxicity. These findings suggest that human CYP2D6 in the brain is protective against beta-carboline-induced neurotoxicity and that the extensive interindividual variability in CYP2D6 expression in human brain may contribute to variation in susceptibility to certain neurotoxin-associated neurodegenerative disorders. Keywords CYP2D6 . Drug metabolism . Neurotoxicity . Harmine . Propranolol
Introduction Marlaina R. Stocco and Cole Tolledo contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12035-020-02050-w) contains supplementary material, which is available to authorized users. * Rachel F. Tyndale [email protected] 1
Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, Ontario, Canada
2
Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
3
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
4
Department of Psychiatry, University of Toronto, 1 King’s College Circle, Toronto, Ontario M5S 1A8, Canada
Members of the cytoch
Data Loading...
