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Thesis Template CYP2D is Functional in the Brain and Alters Haloperidol-Induced Side Effects by Cole Tolledo A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Department of Pharmacology and Toxicology University of Toronto © Copyright by Cole Tolledo 2020 CYP2D is Functional in the Brain and Alters Haloperidol-Induced Side Effects Cole Tolledo Doctor of Philosophy Department of Pharmacology and Toxicology University of Toronto 2020 Abstract The human cytochrome P450 2D6 (CYP2D6) enzyme metabolizes numerous neurotoxins and centrally-acting drugs, including first generation antipsychotics such as haloperidol. These antipsychotics are used to treat schizophrenia and can cause adverse events in patients following acute and chronic intake. CYP2D6 expression in the liver is essentially uninducible and is regulated by genetics, whereas CYP2D6 expression in the brain is dependent on many factors, including CYP2D6 genetic variation, brain-specific induction of CYP2D6, and drug-drug interactions. Variation in human CYP2D6 activity in the brain may alter local drug and metabolite levels sufficiently to change drug response, including therapeutic efficacy and adverse events. This thesis investigated the impact of brain-specific manipulation of CYP2D on haloperidol-induced responses. CYP2D in rat brain (but not in rat liver) was inhibited by 24-hour pre-treatment with intracerebroventricular propranolol and induced by 7-day subcutaneous nicotine treatment. We found that acute haloperidol-induced catalepsy was decreased after inhibiting, and increased after inducing, CYP2D selectively in rat brain. In contrast, chronic haloperidol-induced vacuous chewing movements were increased after inhibiting, and decreased after inducing, CYP2D selectively in rat brain. Further, we investigated human CYP2D6 drug metabolism in vivo using CYP2D6-transgenic mice (TG) which express human CYP2D6 and ii mouse CYP2D, and in wildtype mice (WT). Mouse CYP2D and human CYP2D6 in TG liver, and mouse CYP2D in WT liver, were inhibited by 24-hour pre-treatment with intraperitoneal propranolol. In contrast, a 24-hour pre-treatment with intracerebroventricular propranolol irreversibly inhibited human CYP2D6 in TG brain, but not mouse CYP2D in TG or WT brain; there was no inhibition of hepatic CYP2D in TG or WT. Brain-specific inhibition of human CYP2D6 in TG brain reduced acute haloperidol-induced catalepsy, without affecting plasma haloperidol levels. This thesis demonstrated that CYP2D, including human CYP2D6, in the brain plays a role in in vivo haloperidol-induced responses. We have developed a new tool that enables the investigation of human CYP2D6 in brain on in vivo drug-response. In conclusion, we demonstrated that human CYP2D6 in the brain is functional and sufficiently able to alter drug- induced behaviour, suggesting a role in altering therapeutic efficacy and adverse events in humans. iii Acknowledgments First and foremost, I would like to thank my supervisor, Dr. Rachel Tyndale, for all the guidance and invaluable expertise that she has provided me throughout my PhD. I am thankful for all the feedback that you have given me and for always pushing me to do better. I know that I would be a far less capable researcher without your patient instruction as I navigated my way through PhD. Thanks to your mentorship, I have grown as a scientist, writer, presenter, and critical thinker. The training I have received and the lessons I have learned from this experience will always stay with me and will no doubt be invaluable in the years ahead. I would also like to thank my supervisory committee members, Dr. Ali Salahpour and Dr. Micheline Piquette-Miller. Thank you for your excellent advice these last few years. Your insight has been instrumental in producing this thesis. I also want to thank the Tyndale lab for all the assistance you have given me during my PhD. I want to especially thank Sharon Miksys for all your writing assistance and your willingness to answer my questions, Bin Zhao for running the multitude of samples that I had over the years, and Fariba Baghai Wadji for your patience, care, and your surgical and experimental expertise. Thank you to the Govender family, the family of my better-half, for all the nourishment you have gifted me. Nourishment of the mind, with all of our fun back-and-forth conversations around the dinner table, nourishment of the body, with all of the delicious meals we have enjoyed whenever we came to visit, and nourishment of the soul, with all of your concern for my wellbeing and wishes for my success. I am grateful for your kind efforts to include me in your family. I would like to express my heartfelt gratitude to my best friend and ever-supportive partner, Piara. You have been the pillar of strength that I constantly draw reason and inspiration from. iv Seeing you give your all at whatever you put your mind to motivates me to keep going and to try harder. I am so very lucky to have you in my life. I will always appreciate all of your encouragement and sacrifice to help me get to the finish line. This achievement is only possible because you were always there for me, from beginning until the end. Thank you to my brother, Eiger, for regularly keeping in touch even when we were an ocean apart and for being considerate whenever my schedule got hectic. Lastly, I want to thank my dad for his thoughtfulness and understanding. You taught me that anything worth doing is worth working hard for. I strive to be as diligent and resilient as you. You are dearly missed. v Declaration I, Cole Tolledo, hereby declare that I composed this thesis, that the work contained herein is my own, except where stated otherwise, and that this work has not been submitted for any previous degree. Much of the text included here is taken directly from our published papers (see publication list). vi Cole Tolledo’s Contributions to the Thesis Study 1. “CYP2D enzymatic metabolism in the rat brain alters acute and chronic haloperidol side-effects by different mechanisms”. This work has been published (Miksys et al. Prog. Neuropsychopharmacol. Biol. Psychiatry. 2017). Cole Tolledo designed the ex vivo brain and liver incubation experiments, performed these experiments, and analyzed the data. Cole Tolledo critically reviewed, edited, and approved the final version of the publication. Study 2. “Propranolol is a mechanism-based inhibitor of CYP2D and CYP2D6 in humanized CYP2D6-transgenic mice: effects on activity and drug response”. This work has been published (Tolledo et al. Br. J. Pharmacol. 2020). Cole Tolledo, along with other authors, designed the study. Cole Tolledo optimized and performed the in vitro propranolol inhibition experiments, and optimized and performed the ex vivo liver incubation experiments. Cole Tolledo, with support, collected blood samples for in vivo plasma dextromethorphan and dextrorphan levels after an in vivo 24-hour pre-treatment with intraperitoneal propranolol, performed the acute haloperidol-induced catalepsy experiments, and collected blood samples for in vivo plasma haloperidol levels after an in vivo 24-hour pre-treatment with intraperitoneal propranolol. Cole Tolledo statistically analyzed the data and wrote the manuscript. Study 3. “Human CYP2D6 is functional in brain in vivo: evidence from humanized CYP2D6-transgenic mice”. This work has been published (Tolledo et al. Mol. Neurobiol. 2020). Cole Tolledo, along with other authors, designed the study. Cole Tolledo optimized the ex vivo brain and liver incubation experiments, and performed the ex vivo liver incubation experiments. Cole Tolledo, with support, performed the ex vivo brain incubation experiments, collected and processed brain tissue for in vivo brain dextromethorphan and dextrorphan levels, and collected and processed blood samples for in vivo plasma dextromethorphan and dextrorphan levels after an in vivo 24-hour pre-treatment with intracerebroventricular propranolol. Cole Tolledo, with support, performed the acute haloperidol-induced catalepsy experiments and collected blood samples for in vivo plasma haloperidol levels after an in vivo 24-hour pre- treatment with intracerebroventricular propranolol. Cole Tolledo, and others, performed the cannulation surgeries. Cole Tolledo analyzed the data and wrote the manuscript. Appendix A. “Human CYP2D6 in the brain is protective against harmine-induced neurotoxicity: evidence from humanized CYP2D6 transgenic mice.” This work has been vii submitted. Cole Tolledo, along with other authors, designed the study. Cole Tolledo optimized the ex vivo brain and liver incubation experiments, and performed the ex vivo liver incubation experiments. Cole Tolledo contributed to the ex vivo brain incubation experiments. Cole Tolledo, and others, performed the cannulation surgeries. Cole Tolledo analyzed the ex vivo brain and liver incubation data. Cole Tolledo critically reviewed, edited, and approved the final version of the publication. viii Table of Contents Acknowledgments .................................................................................................... iv Declaration .............................................................................................................. vi Cole Tolledo’s Contributions to the Thesis ........................................................... vii List of Publications ............................................................................................... xiii List of Tables .........................................................................................................
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