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ARNO G. SIRAKI Katz Centre for Pharmacy and Health Research, Rm. 2020-H Faculty of Pharmacy and Pharmaceutical Sciences University of Alberta Edmonton, AB T6G 2E1 Tel: 780 248-1591, Fax: 780 492-1217, E-mail: [email protected] ACADEMIC BACKGROUND Personal information Keywords: free radicals, drug toxicity, peroxidase, electron spin resonance spectroscopy, pharmacology, toxicology, oxidative stress. Citizenship: Canadian Languages: fluent in English and Armenian EDUCATION AND TRAINING NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES, 11/2004 11/2008 RESEARCH TRIANGLE PARK, NC, USA Post-doctoral fellow, Free Radical Metabolite Group. Supervisor: Ronald P. Mason Designed and implemented methods to determine protein free radical formation induced by xenobiotic metabolism in enzymatic and cellular models. Uncovered reactive free radical reactive metabolites that have not been reported. Current research is aimed at colocalization of xenobiotic-induced protein free radicals using confocal microscopy to determine the subcellular location of protein free radical formation. UNIVERSITY OF TORONTO 01/2001 – 11/2004 Doctoral Candidate, Supervisor: Peter J. O’Brien Thesis title: “Development of quantitative structure-activity relationships for metabolic activation of drugs and xenobiotics to reactive metabolites.” Investigated metabolic activation of xenobiotics in isolated rat hepatocytes by modulating biotransformation pathways. Carried out analyses to determine biochemical endpoints mediated by reactive metabolites. Formulated structure-activity relationships to determine the physico-chemical component of cytotoxicity. UNIVERSITY OF TORONTO 09/1998 – 09/2000 MSc Candidate, Supervisor: Peter J. O’Brien Thesis title: “Antioxidant and Pro-Oxidant Nature of Catecholamines” Investigated free radical scavenging of catecholamine-iron complexes in enzymatic and isolated rat hepatocytes. Determined the reactivity of catecholamines and other neurotransmitter reactive free radical metabolites formed by peroxidase enzymes. UNIVERSITY OF TORONTO 09/1997-06/1998 BSc student, 4 th year project supervisor: Christine Forster Fourth year project course involved a model of congestive heart failure focused on determining the levels of α1-adrenergic receptors in the left ventricle of canine hearts.

ARNO G. SIRAKI - University of Alberta · ARNO G. SIRAKI Katz Centre for Pharmacy and Health Research, Rm. 2020-H Faculty of Pharmacy and Pharmaceutical Sciences University of Alberta

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ARNO G. SIRAKI Katz Centre for Pharmacy and Health Research, Rm. 2020-H

Faculty of Pharmacy and Pharmaceutical Sciences University of Alberta

Edmonton, AB T6G 2E1 Tel: 780 248-1591, Fax: 780 492-1217, E-mail: [email protected]

ACADEMIC BACKGROUND

Personal information Keywords: free radicals, drug toxicity, peroxidase, electron spin resonance spectroscopy, pharmacology, toxicology, oxidative stress. Citizenship: Canadian Languages: fluent in English and Armenian EDUCATION AND TRAINING NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES, 11/2004 – 11/2008 RESEARCH TRIANGLE PARK, NC, USA Post-doctoral fellow, Free Radical Metabolite Group. Supervisor: Ronald P. Mason

Designed and implemented methods to determine protein free radical formation induced by xenobiotic metabolism in enzymatic and cellular models.

Uncovered reactive free radical reactive metabolites that have not been reported. Current research is aimed at colocalization of xenobiotic-induced protein free radicals using

confocal microscopy to determine the subcellular location of protein free radical formation. UNIVERSITY OF TORONTO 01/2001 – 11/2004 Doctoral Candidate, Supervisor: Peter J. O’Brien Thesis title: “Development of quantitative structure-activity relationships for metabolic activation of drugs and xenobiotics to reactive metabolites.”

Investigated metabolic activation of xenobiotics in isolated rat hepatocytes by modulating biotransformation pathways.

Carried out analyses to determine biochemical endpoints mediated by reactive metabolites. Formulated structure-activity relationships to determine the physico-chemical component of

cytotoxicity. UNIVERSITY OF TORONTO 09/1998 – 09/2000 MSc Candidate, Supervisor: Peter J. O’Brien Thesis title: “Antioxidant and Pro-Oxidant Nature of Catecholamines”

Investigated free radical scavenging of catecholamine-iron complexes in enzymatic and isolated rat hepatocytes.

Determined the reactivity of catecholamines and other neurotransmitter reactive free radical metabolites formed by peroxidase enzymes.

UNIVERSITY OF TORONTO 09/1997-06/1998 BSc student, 4th year project supervisor: Christine Forster Fourth year project course involved a model of congestive heart failure focused on determining the levels of α1-adrenergic receptors in the left ventricle of canine hearts.

Academic Appointments Assistant Professor (tenure-track), Faculty of Pharmacy & 10/2008 – 07/2014 Pharmaceutical Sciences, University of Alberta, Edmonton, AB Canada Associate Professor, Faculty of Pharmacy & 07/2014 – Pharmaceutical Sciences, University of Alberta, Edmonton, AB Canada Administrative Appointments Safety Committee Chair, Faculty of Pharmacy & 08/2011 - present Pharmaceutical Sciences, University of Alberta, Edmonton, AB Canada Director of Pharmaceutical Sciences Graduate Studies, 08/2013 - present Faculty of Pharmacy & Pharmaceutical Sciences, University of Alberta, Edmonton, AB Canada Acting Director of Graduate Studies – Pharmaceutical Sciences, 06/2011 - 07/2011 Faculty of Pharmacy & Pharmaceutical Sciences, University of Alberta, Edmonton, AB Canada Awards Distinction of Service to ACS Journals (received for 2011 reviews) One of top 25 reviewers for Elsevier (received Jan 2011 for 2010 manuscript reviews) Fellows Award for Research Excellence (FARE) recipient (2008) Fellows Award for Research Excellence (FARE) recipient (2006) Society for Free Radical Biology and Medicine “Young Investigator Award” winner (2005) Natural Sciences and Engineering Research Council (NSERC) Postgraduate Scholar (2002-2004) University of Toronto Open Fellowship – Top-up Award (2003-2004) Society of Toxicology Travel Award (2004) Memberships

Association of Faculties of Pharmacy of Canada (AFPC) Society of Free Radical in Biology and Medicine Society of Toxicology

SERVICE

A. MENTORING AND SUPERVISION OF STUDENTS:

Graduate Students – Completed Training:

Name Degree Period Thesis title Current position Pratik Arvadia MSc 9/2009 – 9/2011 4-aminobenzoic acid

hydrazide mediated inhibition of Micro-peroxidase-11: catalytic inhibition by reactive

Laboratory technician, University of Alberta

metabolites Malyaj Narwaley MSc 9/2009 – 9/2011 Target molecules for

reactive free radical metabolites of aromatic amines

Quality Control Analyst, EMD Serono, A Division of EMD Inc., Edmonton AB

Naif Aljuhani MSc 9/2010 – 12/2012 Enhancement of menadione cytotoxicity by bicarbonate: redox cycling and a possible role for the carbonate radical in quinone cytotoxicity

PhD student, University of Alberta

Argishti Baghdasarian**

MSc 9/2011 – present Using quantitative proteomics for elucidation of key proteins involved in aminoglutethimide-induced cytotoxicity

PhD student, University of Alberta

** awarded a Queen Elizabeth II Graduate Scholarship

Graduate Students – In Training:

Name Degree Period Thesis title Md. Saifur Khan* PhD 9/2011 – present Toxicoproteomic approaches to investigate

idiosyncratic drug reactions Naif Aljuhani PhD 1/2013 - present The role of carbonate radical in xenobiotic

activation * awarded an Alberta Innovates Graduate Student Scholarship valued at $31,500/p.a. (3-year)

Undergraduate students: Name Position Period Current position Samantha Lam Student volunteer 09/2010 – 09/2011 Medical student,

Faculty of Medicine, University of Alberta

Phillip Choi Co-op student 05/2010 – 08/2010 Undergraduate student, McMaster University

Rana Rizk Pharm 498 student 01/2014 – 04/2014 Faculty of Pharmacy, BSc Pharm student

Technicians: Name Period Ervin Hou 02/2014 – 08/2014

Post-doctoral fellows: Name Period Dr. Karim Michail* 09/2010 - present

* awarded Alberta Innovates Clinical Researcher – Clinician Fellowship valued at $70,000/p.a.+$5,000 (RA) (3-years) Examining Committees: Student Name Degree and exam Date of exam Supervisor Waheed Asghar PhD candidacy 09/03/2014 Dr. Jamali Osama Elshenawy PhD candidacy 07/30/2014 Dr. El-Kadi Yousef Bin Jardin PhD candidacy 07/29/2014 Dr. Brocks Nasser Alsaleh MSc defense 03/19/2014 Dr. Seubert Forough Sanaee PhD defense 03/03/2014 Dr. Jamali Muna Murad PhD candidacy 11/14/2013 Dr. Guirguis Advaita Ganguly PhD 08/15/2013 Dr.Loebenberg/Dr. Sunwoo Abdullah Turkistani MSc defense 07/23/2013 Dr. Klotz Arash Falamarzian PhD defense 07/08/2013 Dr. Lavasanifar/Dr. Uludag Issa Amara PhD defense 04/16/2013 Dr. El-Kadi Forough Sanaee PhD candidacy 11/22/2012 Dr. Jamali Mohamed Ben-Eltriki MSc defense 9/14/2012 Dr. Brocks Kamal Al-Hallak PhD defense 9/6/2012 Dr. Loebenberg Mohamed El-Gendy PhD defense 8/28/2012 Dr. El-Kadi Muhammad Sarfraz PhD candidacy 11/4/2011 Dr. Loebenberg Issa Amara PhD candidacy 11/7/2011 Dr. El-Kadi Ziyad Binkathlan PhD defense 7/19/2011 Dr. Lavasanifar Mona Aboutabl PhD defense 6/13/2011 Dr. El-Kadi Arash Falamarzian PhD candidacy 1/11/2010 Dr. Lavasanifar Mohamed El-Gendy PhD candidacy 12/23/2010 Dr. El-Kadi Mona Aboutabl PhD candidacy 1/25/2010 Dr. El-Kadi Srividya Kanduru MSc defense 7/27/2009 Dr. Brocks Anwar Mohamed PhD candidacy 12/18/2010 Dr. El-Kadi Jennifer Billinsky PhD defense 9/15/2009 Dr. Krol (U of Sask) Supervisory Committees: Student Name Degree and Supervisor Period Yomna Eltayebi MSc, Dr. Barakat 2014-present Igor Zlobine MSc, Dr. Seubert 2013-present Harmanpreet Kaur PhD, Dr. El-Bialy 2013-present Abdulrahman Asiri* MSc, Dr. El-Kadi 2012-present Kathy Tang PhD, Dr. Doschak 2012-present Abduallah Turkistani MSc, Dr. Klotz 2011-present Yousef Binjardan MSc, Dr. Brocks 2010-present Forough Sanaee PhD, Dr. Jamali 2009-2014

Muhammad Sarfraz PhD, Dr. Loebenberg 2010-present Osama Elshenawy* PhD, Dr. El-Kadi 2011-present Issa Amara PhD, Dr. El-Kadi 2009-2013 Mohamed BenEltriki MSc, Dr. Brocks 2010-2012 Ziyad Binkhathlan PhD, Dr. Lavasanifar 2009-2011 Mona Aboutabl PhD, Dr. El-Kadi 2009-2011 Mohammed El-Gendy PhD, Dr. El-Kadi 2009-2012 * I am interim supervisor until the primary supervisor returns

B. COMMITTEE SERVICE:

1. University of Alberta a) Animal Care and Use Committee, scientific member (2009-present)

b) Faculty of Pharmacy & Pharmaceutical Sciences

Scholarship and Awards Committee (Jan 2010-present) Graduate Studies and Admissions Committee (Sept 2010-present) Safety Committee (Jan 2010-present); chair, Sept 2011 - present Peer review of teaching – ad hoc committee (Sept 2010-present) Interfaculty Graduate Studentships (Nov 26, 2010) – reviewer

c) Faculty of Medicine & Dentistry

Medical Sciences Graduate Program Committee (Apr 15, 2011) – ext. examiner 2. Society of Free Radical Biology and Medicine – Membership Committee member (2011-present) 3. Canadian Oxidative Stress Consortium – Executive Board Member (May 2012 – present) 4. Co-Chair, Organizer, and Presenter: Workshop Session, Society of Toxicology 51st Annual Meeting,

San Francisco, March 11-15, 2012. “Caught in the Act: Free Radical Detection in Pathways to Toxicity.”

C. TEACHING:

Undergraduate Courses Hours Role Pharm 311 – Radiopharmacy and Diagnostic Imaging** 12 / 9 Coordinator / contributor Pharm 306 – Introductory Biomedical Science 10/6 Coordinator / contributor Pharm 467-567 – Oncology 1 Contributor Pharm 447 - Psychiatry 3 Contributor Pharm 477 – Infectious Disease 2 Contributor Graduate Courses Hours Role Pharm 573 - Analytical Techniques in Pharmaceutical Sciences 3 Coordinator Pharm 630 – Drug Metabolism 3 Contributor Pharm 564 – Toxicology of Xenobiotics and Related Pharmaceutical Agents

10/12 Coordinator / contributor

RESEARCH AND SCHOLARLY ACTIVITY

A. Research Interests

1. The involvement of free radical metabolites of drugs in drug toxicology. Specifically, I am investigating how these metabolites could play a role in the toxicity of drugs, including idiosyncratic drug reactions. I apply biochemical, in vitro, and in vivo methods to carry out these studies. My long-term goal is to develop animal models of various idiosyncratic drug reactions.

2. Quinone cytotoxicity mechanisms. I am interested in studying how quinone cytotoxicity can be modulated by enzymes or other small molecules. This project entails in vitro studies aimed at evaluating these factors using cancer cell lines, primary cells, and gene knockout/knockdown experiments. A portion of these studies is aimed at exploring the peroxidase activity of superoxide dismutase as a specific target in cancer cell lines. My long term goal is to apply these research findings to the toxicity or therapy of various quinone drugs.

3. Mechanisms and intervention strategies of bone marrow toxicity. Investigations are being carried out to determine if free radicals can play a role in the dose-limiting hematoxicity demonstrated by chemotherapeutic agents. Preliminary evidence has suggested that nitrones could be possible candidates to reverse this effect, suggesting a possible role of free radical drug metabolites.

4. The role of myeloperoxidase in drug toxicity. Studies are aimed at testing the involvement of myeloperoxidase in drug toxicity using myeloperoxidase knock-out mice. Validated models will provide a future platform to test for potential co-therapies that can attenuate myeloperoxidase toxicity reactions during drug therapy.

B. Research Grants

Awarded: October 2008 – October 2013* $249,000/yr, 3 yr* K99/R00 Pathway to Independence Award – National Institutes of Health “Mechanisms of Aniline-Induced Agranulocytosis” (Grant No.: 1K99-ES017043-01) *Award declined due to employment at a non-U.S. institution October 2009 – September 2012 (extended to March 2015) Operating Grant – Canadian Institutes of Health Research $405,000/3yr “Mechanisms of Drug-Induced Agranulocytosis” (Ref. No.: 202034) 2010 – 2015 Leaders Opportunity Fund – Canadian Foundation for Innovation (CFI) $897,484 “Mechanisms of Drug Free Radical Metabolite Toxicity” CFI – $358,939 VPR-University of Alberta – Matching Funds – $358,939 Faculty of Pharmacy, University of Alberta – $22,144 Vendor In-kind contributions – $157,492 2012-2014 Infrastructure Operating Fund – Canadian Foundation for Innovation $89,736 “Mechanisms of Drug Free Radical Metabolite Toxicity” 2014-2019 Natural Sciences and Engineering Research Council – Discovery Grant $165,000 “The role of electron transfer reactions in the cytotoxicity mechanism of xenobiotics”

C. Research community Evaluation of Manuscripts:

Journal of Biomedicine and Biotechnology PLoS ONE Toxicology Letters Chemico-Biological Interactions Canadian Journal of Physiology and Pharmacology Chemical Research in Toxicology Journal of Pharmacy and Pharmaceutical Sciences Mini Reviews in Medicinal Chemistry Mutation Research-Genetic Toxicology and Environmental Mutagenesis Hypothesis

D. Publications Refereed Publications (trainees underlined)

1. Siraki AG, Smythies J, O'Brien PJ. Superoxide radical scavenging and attenuation of hypoxia-reoxygenation injury by neurotransmitter ferric complexes in isolated rat hepatocytes. Neuroscience Letters. (2000) 296:37-40.

2. Chan TS, Moridani M, Siraki AG, Scobie H, Beard K, Eghbal MA, Galati G, O'Brien PJ. Hydrogen peroxide supports hepatocyte P450 catalysed xenobiotic/drug metabolic activation to form cytotoxic reactive intermediates. Advances in Experimental Medicine & Biology. (2001) 500:233-6.

3. Siraki AG, Pourahmad J, Chan TS, O’Brien PJ. Endogenous and endobiotic induced reactive oxygen species formation by isolated hepatocytes. Free Radical Biology and Medicine. (2002) 32:2-10.

4. Siraki AG, O'Brien PJ. Prooxidant activity of free radicals derived from phenol-containing neurotransmitters. Toxicology. (2002) 177:81-90.

5. Siraki AG, Chan TS, Galati G, Teng S, O’Brien PJ. N-Oxidation of Aromatic Amines by Intracellular Oxidases. Drug Metabolsim Reviews. (2002) 34:549-64.

6. Niknahad H, Siraki AG, Shuhendler A, Khan S, Teng S, Galati G, Easson P, Poon R. and O’Brien PJ. Modulating carbonyl cytotoxicity in intact rat hepatocytes by inhibiting carbonyl metabolizing enzymes. I. Aliphatic alkenals. Chemico-Biological Interactions. (2003) 143-144: 107-17.

7. Niknahad H, Shuhendler A, Galati G, Siraki AG, Easson E, Poon R, O'Brien PJ. Modulating carbonyl cytotoxicity in intact rat hepatocytes by inhibiting carbonyl metabolizing enzymes. II. Aromatic aldehydes. Chemico-Biological Interactions. (2003) 143-144:119-28.

8. Moridani MY, Pourahmad J, Bui H, Siraki AG, O’Brien PJ. Dietary flavonoid iron complexes as cytoprotective superoxide radical scavengers. Free Radical Biology and Medicine. (2003) 34:243-253.

9. Moridani MY, Siraki A, O'Brien PJ. Quantitative structure toxicity relationships for phenols in isolated rat hepatocytes. Chemico-Biological Interactions. (2003) 145:213-223.

10. Moridani MY, Siraki AG, Chevaldina T, Scobie H, O'Brien PJ. Quantitative structure toxicity relationships for catechols in isolated rat hepatocytes. Chemico-Biological Interactions (2004) 147:297-307.

11. Siraki AG, Chan TS, O’Brien PJ. Application of quantitative structure-toxicity relationships for the comparison of p-benzoquinones cytotoxicity in primary cultured rat hepatocytes versus PC12 cells. Toxicological Sciences (2004) 81:148-59.

12. Sabzevari O, Galati G, Moridani MY, Siraki AG, O’Brien PJ. Molecular cytotoxic mechanisms of anticancer hydroxychalcones. Chemico-Biological Interactions. (2004) 148:57-67.

13. Siraki AG, Chevaldina T, O'Brien PJ. Application of quantitative structure-toxicity relationships for acute NSAID cytotoxicity in rat hepatocytes. Chemico-Biological Interactions. (2005) 151:177-91.

14. Schultz TW, Carlson RE, Cronin MT, Hermens JL, Johnson R, O'Brien PJ, Roberts DW, Siraki AG, Wallace KB, Veith GD. A conceptual framework for predicting the toxicity of reactive chemicals: modeling soft electrophilicity. SAR and QSAR in Environmental Research (2006) 17:413-28.

15. Bonini MG, Siraki AG, Atanassov BS, Mason RP. Immunolocalization of hypochlorite-induced, catalase-bound free radical formation in mouse hepatocytes. Free Radical Biology & Medicine (2007) 42:530-40.

16. Bonini MG, Siraki AG, Bhattacharjee S, Mason RP. Glutathione-induced radical formation on lactoperoxidase does not correlate with the enzyme's peroxidase activity. Free Radical Biology & Medicine (2007) 42:985-92.

17. Siraki AG, Bonini MG, Jiang J, Ehrenshaft M, Mason RP. Aminoglutethimide-Induced Protein Free Radical Formation On Myeloperoxidase: A Potential Mechanism Of Agranulocytosis. Chemical Research in Toxicology (2007) 20:1038-1045.

18. Siraki AG, Deterding LJ, Bonini MG, Jiang J, Ehrenshaft M, Tomer KB, Mason RP. Procainamide, but not N-Acetylprocainamide, Induces Protein Free Radical Formation On Myeloperoxidase: A Potential Mechanism Of Agranulocytosis. Chemical Research in Toxicology (2008) 21:1143-1153.

19. Brimfield AA, Mancebo AM, Mason RP, Jiang J, Siraki AG, Novak MJ. Free radical production from the interaction of 2-chloroethyl vesicants (mustard gas) with pyridine nucleotide-driven flavoprotein electron transport systems. Toxicology & Applied Pharmacology. (2009) 234:128-34.

20. Siraki AG, Jiang J, Mason RP. Investigating the Mechanisms of Aromatic Amine-Induced Protein Free Radical Formation by Quantitative Structure-Activity Relationships: Implications for Drug-Induced Agranulocytosis. Chemical Research in Toxicology. (2010) 23:880-887.

21. Narwaley M, Michail K, Arvadia P, Siraki AG. Drug-Induced Protein Free Radical Formation Is Attenuated by Unsaturated Fatty Acids by Scavenging Drug-Derived Phenyl Radical Metabolites. Chemical Research in Toxicology. (2011) 24:1031-9.

22. Arvadia P, Narwaley M, Whittal RM, Siraki AG. 4-Aminobenzoic acid hydrazide inhibition of microperoxidase-11: Catalytic inhibition by reactive metabolites. Archives of Biochemistry and Biophysics. (2011) 515(1-2):120-6.

23. Michail K, Siraki AG. Post-trapping Derivatization of Radical-derived EPR-silent Adducts: Application to Free Radical Detection by HPLC-UV in Chemical, Biochemical, and Biological Systems and Comparison with EPR Spectroscopy. Analytical Chemistry. (2012) 84:6739-46.

24. Michael AM, Lotfy HM, Reda MR, Michail K, Somayaji V, Siraki AG, El-Kadi AOS, Shehata MA. Simultaneous Determination of Sumatriptan and Naproxen in Dosage Forms and Human Plasma Using LC/MS. Current Analytical Chemistry. (2012) 8:512-519.

25. El Gendy MAM, Ali BH, Michail K, Siraki AG, El-Kadi AOS. Induction of quinone oxidoreductase 1 enzyme by Rhazya stricta through Nrf2-dependent mechanism. Journal of Ethnopharmacology. (2012). 144:416-424.

26. Michail K, Siraki AG. The Interaction of Diamines and Polyamines with the Peroxidase-catalyzed Metabolism of Aromatic Amines – A Potential Mechanism for Modulation of Aniline Toxicity. Canadian Journal of Physiology and Pharmacology (2012) 91:228-35.

27. Aljuhani N, Michail K, Karapetyan Z, Siraki AG. The effect of bicarbonate on menadione-induced redox cycling and cytotoxicity: potential involvement of the carbonate radical. Canadian Journal of Physiology and Pharmacology (2013) 91:783-90.

28. Michail K, Baghdasarian A, Khan MS, Aljuhani N, Narwaley M, Siraki AG. Scavenging of Free-

Radical Metabolites of Aniline Xenobiotics and Drugs by Amino Acid Derivatives: Toxicological

Implications of Radical-Transfer Reactions. Chemical Research in Toxicology (2013) 26:1872-83.

29. Khan Md.S., Fahlman R., Baghdasarian A., Michail K., Siraki AG. Current status and future

prospects of toxicogenomics in drug discovery. Drug Discovery Today (2013) Available online 8

November 2013.

Reviews, and Book Chapters 30. Siraki AG, Chevaldina T, Moridani MY, O'Brien PJ. Quantitative structure-toxicity relationships by

accelerated cytotoxicity mechanism screening. Current Opinion in Drug Discovery & Development

(2004) 7:118-25. 31. O'Brien PJ, Siraki AG. Accelerated cytotoxicity mechanism screening using drug metabolising

enzyme modulators. Current Drug Metabolism. (2005) 6:101-9. 32. O’Brien PJ, Siraki AG, Shangari N. Aldehyde Sources, Metabolism, Molecular Toxicity, Mechanisms,

and Possible Effects on Human Health. Critical Reviews in Toxicology. (2005) 35:609–662. 33. Siraki AG, Ehrenshaft M. Endogenous macromolecule radicals in Endogenous Toxins. Diet,

Genetics, Disease and Treatment., (editors: R. Bruce, P.J. O’Brien) WILEY-VCH Verlag GmbH & Co. KGaA (Weinheim) pp.65-100 (2010).

34. Siraki AG. Free radical metabolites in arylamine toxicity in Advances in Molecular Toxicology- Volume 7., (editor: James Fishbein) 2013, pp.39-82.

Manuscripts in preparation or submitted

1. Michail K, Baghdasarian A, Khan MS, Aljuhani N, Narwaley M, Siraki AG. The effect of dimethylglycine in electron transfer between N-centered aromatic amine free radicals. (In preparation)

2. Baghdasarian A., Michail K., Narwaley M, Siraki AG. Tryptophan residues are targets for reactive free radical metabolites of aminoglutethimide. (In preparation)

3. Khan Md.S., Baghdasarian A., Fahlman R., Michail K., Siraki AG. Quantitative proteomic analysis of HL-60 cells treated with isoniazid reveals a balance between toxicity and defense pathways.

4. Baghdasarian A., Khan Md.S., Fahlman R., Michail K., Siraki AG. Quantitative Proteomic Analysis (SILAC) Reveals Aminoglutethimide Induced the Expression of Apoptotic & Oxidative Stress Proteins: A Potential Insight into Drug-Induced Agranulocytosis. (submitted to Chem-Biol Int)

Abstracts - Poster and/or Oral Presentations (trainees underlined):

1. Siraki AG, Chan TS, O’Brien L, Parekh K, O’Brien PJ. Dopamine metabolic activation by manganese (II) versus P450 peroxygenase activity. Oxidative Stress Consortium, Hamilton, ON (March 14-16, 2000).

2. Siraki AG, Chan TS, O’Brien L, Parekh K, O’Brien PJ. Manganese (II) as a selective catalyst for dopamine toxicity: possible mechanism for metal-induced Parkinson’s disease. Canadian Federation of Biological Societies, Ottawa, ON (June 22-25, 2000).

3. Galati G, Siraki AG, Chan TS, Moridani MY, O’Brien PJ. Phenoxyl radical mediated prooxidant and cytotoxic mechanisms. Society of Toxicology Annual Meeting, San Francisco, CA (March 25-29, 2001).

4. Siraki AG, Chan TS, O’Brien PJ. Cytotoxic mechanisms of dopamine vs. tyramine: the importance of one hydroxyl group. Oxidative Stress Consortium, London, Canada (May 3-6, 2001).

5. Siraki AG and O’Brien PJ. Dopamine as the cause and cure for Parkinson’s disease: a novel biochemical pathway for dopamine-induced cell death. Armenian Medical World Congress, Toronto, Canada (July 4-8, 2001).

6. Siraki AG and O’Brien PJ. Application of Quantitative Structure-Activity Relationships in Toxicology. Oxidative Stress Consortium Trainee Meeting, Hamilton, Canada (Aug 22, 2001).

7. Siraki AG, Galati G, Chan TS, O’Brien PJ. Application of a NADH Oxidation Assay to calculate redox potential & cytotoxic activity of aromatic amines. 5th International Symposium on the Biological Oxidation of Nitrogen in Organic Molecules, Munich, Germany (Oct 4-6, 2001).

8. Siraki AG, Moridani MY, Chevaldina T, O’Brien PJ. Quantitative structure toxicity relationships for phenols evaluated with isolated rat hepatocytes. International Society for the Study of Xenobiotics, Munich, Germany (Oct 7-11, 2001): Drug Metabolism Reviews. 2001 33 supp1:234.

9. Siraki AG, Raymond Poon, and Peter J. O’Brien. i) The intracellular origin of reactive oxygen species induced by polyhalogenated aromatic hydrocarbons; ii) Metal versus endobiotic induced cellular reactive oxygen species formation by isolated hepatocytes: new techniques for locating the intracellular source; iii) The intracellular origin of reactive oxygen species induced by urban air nitroaromatics. (3 posters presented). Toxic Substances Research Initiative (National

Conference), Ottawa, Canada (March 5-8, 2002). 10. Siraki AG and O’Brien PJ. Involvement of reactive oxygen species in the toxicity/carcinogenicity of

nitroaromatic/quinone urban air toxins and idiosyncratic drugs. Oxidative Stress Consortium, Saskatoon, Canada (May 2-5, 2002).

11. Siraki AG, Hossein Niknahad, Adam Shuhendler, Giuseppe Galati and Peter J. O’Brien. Physicochemical determinants of aldehyde toxicity. Graduate Research in Progress, University of Toronto, (Mar 2003).

12. Chan TS, Teng S, Moridani M, Siraki AG, O’Brien PJ. The role of aldehyde dehydrogenase in the prevention of formaldehyde mediated norsalsolinol formation in PC12 cells. Journal of Neurochemistry (2003) 87 (Suppl. 1): 140 (P13-58).

13. Siraki AG and Peter J. O’Brien. QSAR of p-benzoquinones in rat hepatocytes. Society of Toxicology of Canada, Montreal, Canada (Dec 8-9, 2003).

14. Siraki AG and Peter J. O’Brien. Classical and 3D Quantitative Structure-Activity Relationships: application to acute benzoquinone toxicity in vitro. Oxidative Stress Consortium Trainee Meeting, Toronto, Ont (Aug 24, 2004).

15. Siraki AG, T.S. Chan, and Peter J. O’Brien. Application of QSARs to evaluate the cytotoxic mechanisms of p-benzoquinones in rat primary hepatocytes and PC12 cells. Society of Toxicology, Baltimore MD (Mar 22-25, 2004).

16. Siraki AG, Marcelo G. Bonini, and Ron P. Mason. Biting the hand that feeds: use of a novel DMPO-protein antibody in detection of a drug-induced myeloperoxidase radical adduct upon myeloperoxidase-catalyzed peroxidation of aminoglutethimide. SFRBM annual meeting, Austin TX. Nov 18, 2005.

17. Siraki AG, Marcelo G. Bonini, Jin Jie Jiang, and Ron P. Mason. Novel activity of the anti-cancer drug aminoglutethimide: possible insights into a mechanism for agranulocytosis. FARE 2005.

18. Siraki AG, Marcelo G. Bonini, Jin Jie Jiang, and Ron P. Mason. Aminoglutethimide-Induced Protein Free-Radical Formation on Myeloperoxidase - A Possible Mechanism of Agranulocytosis. SFRBM annual meeting, Washington DC. Nov 19, 2007.

19. Siraki AG, Marcelo G. Bonini, Jin Jie Jiang, and Ron P. Mason. Aminoglutethimide-Induced Protein Free-Radical Formation on Myeloperoxidase - A Possible Mechanism of Agranulocytosis. AstraZeneca, Sodertalje, Sweden. August 17, 2006.

20. Siraki AG, Marcelo G. Bonini, Jin Jie Jiang, and Ron P. Mason. Aminoglutethimide-Induced Protein Free-Radical Formation on Myeloperoxidase - A Possible Mechanism of Agranulocytosis. Jan 29, 2007. PDF Summer Symposium. Jun 29, 2007.

21. Siraki AG, Leesa Deterding, Marcelo G. Bonini, JinJie Jiang, Marilyn Ehrenshaft, Ronald P. Mason. Drug induced protein free radical formation on myeloperoxidase: a potential mechanism of agranulocytosis. PDF Summer Symposium. Jun 10, 2008.

22. Malyaj Narwaley, Pratik Arvadia, Siraki AG. In vitro evidence of phenyl radical metabolite formation by aniline based drugs due to peroxidase metabolism and their reactivity as a cause for agranulocytosis. Nov 20, 2009. Pharmaceutical Sciences Research Day. University of Alberta.

23. Pratik Arvadia, Malyaj Narwaley, Siraki AG. Formation of neutrophil myeloperoxidase protein free radicals by myeloperoxidase catalyzed metabolism of captopril as a possible mechanism of agranulocytosis. Nov 20, 2009. Pharmaceutical Sciences Research Day. University of Alberta.

24. Malyaj Narwaley, Pratik Arvadia, Siraki AG. Unsaturated lipids as potential intra-cellular target of phenyl radical metabolite generated during peroxidase metabolism of aromatic amine xenobiotics. Sep 24-26, 2010. Western Canadian Medicinal Chemistry Workshop, University of Saskatchewan. (Awarded best poster)

25. Pratik Arvadia, Malyaj Narwaley, Siraki AG. Microperoxidase-11, a model system to identify the mechanism of myeloperoxidase inhibition by 4-aminobenzoic acid hydrazide. Sep 24-26, 2010. Western Canadian Medicinal Chemistry Workshop, University of Saskatchewan.

26. Siraki AG, JinJie Jiang, Ronald P. Mason. Investigating the mechanisms of aromatic amine-induced protein free radical formation by QSARs: implications for drug-induced agranulocytosis. March 6-

10, 2011. Society of Toxicology, Washington, DC. 27. Pratik Arvadia, Malyaj Narwaley, Randy Whittal, Siraki AG. Microperoxidase-11 inhibition by 4-

aminobenzoic acid hydrazide via free-radical metabolites : A model to study the myeloperoxidase inhibition. May 18-20, 2011. Appled Pharmaceutical Toxicology, San Francisco, CA.

28. Pratik Arvadia, Malyaj Narwaley, Randy Whittal, Siraki AG. 4-Aminobenzoic acid hydrazide inhibition of microperoxidase-11: catalytic inhibition by reactive metabolites. 7th International Human Peroxidase Meeting, Brussels, Belgium. May 22-25, 2011 (Selected oral presentation).

29. Malyaj Narwaley, Pratik Arvadia, Siraki AG. Drug-induced protein free radical formation is attenuated by linoleic acid by scavenging drug-derived phenyl radical metabolites. May 24-27, 2011. Canadian Society for Pharmaceutical Sciences, Montreal, QC.

30. Siraki AG, Malyaj Narwaley, Karim Michail, Pratik Arvadia. Free radical metabolites of aromatic amine drugs: characterization, consequences, and potential toxicity. September 26-29, 2011. 6th SPIN Conference, Marseille, France.

31. Karim Michail, Siraki AG. HPLC determination of 5,5-dimethyl-1-pyrroline N-oxide free radical-derived adducts after derivatization of the electron paramagnetic resonance-silent species: Application to chemical and biochemical model systems. November 16-20, 2011. 18th Annual Meeting of the Society of Free Radical Biology and Medicine. Atlanta, GA. (Selected oral presentation – K.Michail awarded travel award).

32. Naif Aljuhani, Siraki AG. Enhancement of menadione cytotoxicity by bicarbonate: redox cycling and a possible role for the carbonate radical in quinone cytotoxicity. 7th Meeting of the Canadian Oxidative Stress Consortium. May 10-12, 2012, Thunder Bay, ON. (Selected oral presentation)

33. Karim Michail, Siraki AG. The interaction of Aminocarboxylates and Polyamines with Aromatic Amine-derived Free Radicals – Potential Modulators for Aniline Toxicity. 7th Meeting of the Canadian Oxidative Stress Consortium. May 10-12, 2012, Thunder Bay, ON. (Selected oral presentation – K.Michail awarded travel award)

34. Karim Michail, Siraki AG. Endogenous Metabolites Modulate Macromolecular Free Radicals Derived from Aromatic Amine Drugs in Neutrophil-like Myeloid Leukemia Cells. 19th Annual Meeting of the Society of Free Radical Biology and Medicine. Nov 14-18, 2012. San Diego, CA. (K.Michail awarded travel award).

35. Argishti Baghdasarian, Karim Michail, Siraki AG. Induction of aminoglutethimide-mediated protein radical formation by N,N-dimethylglycine through a homocysteine-dependent mechanism: potential implications for drug-induced agranulocytosis. Society of Toxicology of Canada, 44th Annual Symposium. Dec 2-4, McGill University. (AB received travel award).

36. Karim Michail, Siraki AG. Scavenging of Arylamine-derived Free Radicals by Amino Acid Derivatives: Toxicological Implications of Radical Transfer Reactions. 6th Annual PSRC meeting, June 16-20, 2013, Vancouver, BC.

37. Saifur R. Khan, Arigshti Baghdasarian, and Siraki AG. Proteomic insight of isoniazid immunomodulatory activity: considerations for tuberculosis therapy. Society of Toxicology Annual Meeting. March 23-27, 2014, Phoenix, AZ.

Invited Presentations:

1. September 18, 2009. “Potential role of free radical metabolites in drug-induced agranulocytosis.” Faculty of Pharmacy and Nutrition, University of Saskatchewan.

2. January 8, 2010. “Reactive Free Radical Metabolites: A hypothesis of their potential to induce adverse drug reactions.” Leslie Dan Faculty of Pharmacy, University of Toronto.

3. May 4, 2010. “Possible Involvement of Free Radical Metabolites in the Etiology of Drug‐Induced Agranulocytosis.” Joint conference of the 14th In Vivo EPR Spectroscopy and Imaging and 11th International EPR Spin Trapping/Spin Labeling Conference (EPR 2010).

4. February 25, 2011. “Caught in the Act: Free Radical Detection and Implications in Toxicology.” Analytical & Environmental Toxicology Research Group, University of Alberta.

5. April 20, 2011. “Tricks and traps: detecting free radicals for studies in the Pharmaceutical

Sciences.” Canadian Society of Pharmaceutical Sciences, Webinar. 6. September 22, 2011. “Free radical metabolites of aromatic amine drugs: cellular targets and

functional relevance.” Mini-Symposium - Recent Developments in Pharmaceutical Sciences: Oxidative Stress and cell signalling. University of Alberta, Faculty of Pharmacy & Pharmaceutical Sciences.

7. April 3, 2012. “Aniline-Based Drugs – Merging Free Radical Metabolites with Side-Effects.” Toxicology program seminar, University of Guelph.

8. April 11, 2012. “ESR Applications in Toxicology.” Leslie Dan Faculty of Pharmacy, University of Toronto.

9. May 11, 2012. “Free radical metabolites of aniline-based drugs –implications for toxicity.” 7th Meeting of the Canadian Oxidative Stress Consortium. Lakehead University, Thunder Bay, ON

10. December 3, 2012. “Myeloperoxidase - the good and the bad for drug toxicity.” Centre de Recherche BioMed, Université du Québec à Montréal.

11. August 14-15, 2013. “The interaction of aniline free radical metabolites with polyamines and polyaminocarboxylates: differential metabolic fate and electron transfer reactions.” 10th International Symposium on Persistent Toxic Substances (ISPTS), University of Alberta.

12. February 9-14, 2014. “The role of neutrophil myeloperoxidase drug oxidation in the development of autoimmunogens.” The Oxygen Radicals Gordon Research Conference, Ventura Beach, CA.

VOLUNTEER AND PUBLIC SERVICE May 11, 2011 - PGSA Workshop: Working in National/ State Laboratories (Canada/ US). Panel presenter. I had a candid discussion with students thinking about the next step in their careers, answered questions, and offered advice. November 25, 2011; November 9, 2012 - Poster judge for Research Day at the Faculty of Pharmacy & Pharmaceutical Sciences April 11, 2013 – Teaching microscopy to Grade 1 student at Esther Starkman Public School. May 30, June 4, June 6 – Volunteering at Esther Starkman Public School (for student supervision). January 30, 2014 – Emcee for the White Coat ceremony – the first event in the centennial anniversary celebration of the Faculty of Pharmacy & Pharmaceutical Sciences, University of Alberta.