Nakatsu, Kanji - Queen's University - Department of Biomedical and Molecular Sciences

个人简介

While my present research has its roots in cardiovascular pharmacology, it now applies also to other areas of pharmacology, including cancer and CNS. My research interests lie in the pharmacology of carbon monoxide (CO) and heme oxygenase (HO), and how CO as well as selective inhibitors and activators of HO isozymes can be developed for human use. This has evolved from earlier research on the pharmacology of organic nitrate vasodilators (nitroglycerin, glyceryl trinitrate) and nitric oxide (NO). HO catabolizes heme to liberate CO, biliverdin and iron. My training in pharmacology was received at the University of Alberta (MSc), University of British Columbia (PhD) and Stanford University (Postdoc). I have been a member of Queen's School of Medicine since 1973.

研究领域

Cardiovascular Pharmacology & Drug Design While my present research has its roots in cardiovascular pharmacology, it now applies also to other areas of pharmacology, including cancer and CNS. My research interests lie in the pharmacology of carbon monoxide (CO) and heme oxygenase (HO), and how CO as well as inhibitors and activators of HO can be developed for human use. This has evolved from earlier research on the pharmacology of organic nitrate vasodilators (nitroglycerin, glyceryl trinitrate) and nitric oxide (NO). HO catabolizes heme to liberate CO, biliverdin and iron, one of the questions that we addressed previously was the importance of the availability of heme for HO as well as other heme-requiring enzymes in the context of hypertension. In our earlier work on CO and other gasotransmitters, the requirement for better pharmacological tools to study the HO system became a progress-limiting impediment. This led to our present research, which focuses on the creation and application of novel inhibitors of HO, both HO-1 and HO-2, and activators of HO-1 and HO-2. Some of our new compounds have been observed to be selective for inhibition of the inducible isoform, HO-1, and others show selectivity for the constitutive isoform, HO-2. These second generation HO inhibitors are being investigated for their application to various disease states for which current pharmacological treatment requires significant improvement. In parallel with our work on HO inhibitors, we have identified drugs that selectively activate HO-2, and others that activate both HO-1 and HO-2. This work is done in collaboration with Drs. James Brien, Zhongchao Jia & Bruce Elliott, School of Medicine; Dr. Walter Szarek, Department of Chemistry; off campus private sector companies. Other members of the research team are: Maaike Hum, Brian McLaughlin, and Drs. Mona Rahman and Dragic Vukomanovic. I am also participating in clinical research projects that involve CO and HO; the principal investigators for these projects are Drs. Paul Belliveau & Darrin Payne, Surgery. We are grateful to Canadian taxpayers for their support through the Canadian Institutes of Health Research; we also recognize donors to the Heart & Stroke Foundation of Ontario for their support of many earlier publications.

近期论文

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1.K. Nakatsu and R.J. Reiffenstein. Increased receptor utilization: Mechanism of cocaine potentiation. Nature, 217: 1276-1277, 1968. 2.K. Nakatsu and G.I. Drummond. Adenylate metabolism and adenosine formation in the heart. Amer. J. Physiol., 223: 1119-1127, 1972. 78. G.S. Marks, J.F. Brien, K. Nakatsu and B.E. McLaughlin. Does carbon monoxide have a physiological function? Trends Pharmacol. Sci. 12: 185-188, 1991.148.R.T. Kinobe, Y. Ji, Jason Z. Vlahakis, Roberto Motterlini, James F. Brien, Walter A. Szarek and Kanji Nakatsu. Effectiveness of Novel Imidazole-dioxolane Heme Oxygenase Inhibitors in Renal Proximal Tubule Epithelial Cells. J. Pharmacol. Exp. Ther. 323:763-770, 2007. 149.Roman G, Riley JG, Vlahakis JZ, Kinobe RT, Brien JF, Nakatsu K, Szarek WA. Heme oxygenase inhibition by 2-oxy-substituted 1-(1H-imidazol-1-yl)-4-phenylbutanes: effect of halogen substitution in the phenyl ring. Bioorg Med Chem. 2007 May 1;15(9):3225-34. Epub 2007 Feb 22. 150.Stephane L Bourque, Marina Komolova, Kanji Nakatsu, Michael A Adams. The long-term circulatory consequences of perinatal iron-deficiency in male Wistar rats. Hypertension 51: 154-159, 2007. 151.Stephane L Bourque, Umar Iqbal, James Reynolds, Michael A Adams, Kanji Nakatsu* Perinatal iron-deficiency induces cognitive and locomotor behavioural changes in adult male, but not female rats. J. Nutrition. 138:931-7, 2008. 152.Dick E. Zoutman, B. Douglas Ford, Assil R. Bassili, Jarold L. Cosby, Kanji Nakatsu. Factors Affecting Antibiotic Decisions for Upper Respiratory Tract Infections I: A Survey of Family Physicians. International Journal of Infection Control 4(1) 1-7, 2008. 153.Dick E. Zoutman, B. Douglas Ford, Assil R. Bassili, Jarold L. Cosby, Kanji Nakatsu. Factors Affecting Antibiotic Decisions for Upper Respiratory Tract Infections II: A Survey of Patients. International Journal of Infection Control (In press). 154.J. Soong, MA Adams, K Nakatsu. Acute depletion of heme by succinylacetone alters vascular responses but does not induce hypertension. Can J Physiol Pharmacol 86: 613-619, 2008. 155.RT Kinobe, RA Dercho, K Nakatsu. Inhibitors of the Heme Oxygenase—Carbon Monoxide System: On the Doorstep of the Clinic?, Can J Physiol Pharmacol 86: 577-599, 2008. 156.M Komalova, SL Bourque, K Nakatsu, MA Adams. Sedentariness and increased visceral adiposity in adult perinatally iron-deficient rats. International Journal of Obesity 32:1441-1444, 2008. 157.Jason Z. Vlahakis, Maaike Hum, Mona N. Rahman, Zongchao Jia, Kanji Nakatsu and Walter A. Szarek, Synthesis and evaluation of imidazole–dioxolane compounds as selective heme oxygenase inhibitors: Effect of substituents at the 4-position of the dioxolane ring. Bioorg Med Chem.:2461-75, 2009. 158.Mona N. Rahman, Jason Z. Vlahakis, Walter A. Szarek, Kanji Nakatsu, Zongchao Jia. X-ray crystal structure of human heme oxygenase-1in complex with 1-(adamantan-1-yl)-2-(1h-imidazol-1-yl)ethanone: a common binding mode for imidazolebased heme oxygenase-1 inhibitors. J. Med. Chem. 2008, 51, 5943–5952. 159.Mona N. Rahman, Jason Z. Vlahakis, Dragic Vukomanovic, Walter A. Szarek, Kanji Nakatsu, and Zongchao Jia. X-ray Crystal Structure of Human Heme Oxygenase-1with (2R,4S)-2-[2-(4-Chlorophenyl)ethyl]-2-[(1Himidazol-1-yl)methyl]-4[{(5-trifluoromethylpyridin-2-yl)thio}methyl]-1,3-dioxolane:A Novel, Inducible Binding Mode. J. Med. Chem. 2009, 52, 4946–4950. 160.Mona N Rahman, Jason Z Vlahakis, Gheorghe Roman, Dragic Vukomanovic, Walter A Szarek, Kanji Nakatsu, Zongchao Jia.Structural Characterization of Human Heme Oxygenase-1 in Complex with Azole-based Inhibitors. J Inorg Biochem. 2010 Mar;104(3):324-30. Epub 2009 Oct 24. Review.PMID: 19917515 161.Gheorghe Roman, Mona N. Rahman, Dragic Vukomanovic, Zongchao Jia, Kanji Nakatsu and Walter A. Szarek. Heme Oxygenase Inhibition by 2-Oxy-substituted 1-Azolyl-4-phenylbutanes: Effect of Variation of the Azole Moiety. X-Ray Crystal Structure of Human Oxygenase-1 in Complex with 4-Phenyl-1-(1H-1,2,4-triazol-1-yl)-2-butanone. Chemical Biology & Drug Design 75: 68-90, 2010. PMID: 19954435 162.Dragic Vukomanovic1, Brian McLaughlin1, Mona N. Rahman2, Jason Z. Vlahakis3, Gheorghe Roman3, James F. Brien1, Zongchao Jia2, Walter A. Szarek3, and Kanji Nakatsu1* Recombinant Truncated and Microsomal Heme Oxygenase-1 and -2: Differential Sensitivity to Inhibitors. Can J Physiol Pharmacol 2010 Apr;88(4):480-6. PMID: 20555417 163.Stephane L Bourque, Michael A Adams, Kanji Nakatsu, Andrew Winterborn. Comparison of Buprenorphine and Meloxicam for Post-Surgical Analgesia; effect on body weight, ambient locomotor activity and hemodynamic parameters. J Am Assoc Lab Anim Sci. 2010;49(5):617-22.PMID: 20858364 164.Stephane L Bourque†, Carling D Benjamin†, Michael A Adams, Kanji Nakatsu*. Lack of Hemodynamic Effects of Extended Heme Synthesis Inhibition by Succinylacetone in Rats. J Pharmacol Exp Ther 333: 290-296, 2010. PMID: 20071481 165.Maaike Hum, Brian E McLaughlin, Gheorghe Roman, Jason Z Vlahakis, Walter A Szarek, Kanji Nakatsu. The Effects of Azole-Based Heme Oxygenase Inhibitors on Rat Cytochromes P450 2E1 & 3A1/2 and Human Cytochromes P450 3A4 & 2D6. J Pharmacol Exp Ther. 2010 Sep 1;334(3):981-7. Epub 2010 May 25.PMID: 20501634 166.Vlahakis JZ, Rahman MN, Roman G, Jia Z, Nakatsu K, Szarek WA. Rapid, convenient method for screening imidazole-containing compounds for heme oxygenase inhibition. J Pharmacol Toxicol Methods. 63(1):79-88, 2011. Epub 2010 Jun 4.]PMID: 20561893 167.Roman G, Vlahakis JZ, Vukomanovic D, Nakatsu K, Szarek WA. Heme oxygenase inhibition by 1-aryl-2-(1h-imidazol-1-yl/1h-1,2,4-triazol-1-yl)ethanones and their derivatives. ChemMedChem. 2010 Sep 3;5(9):1541-55.PMID: 20652928 168.Milne B,VanDenKerkhof EG, Phelan R, Brien JF, Forkert L, Nakatsu K. Does Carbon Monoxide Play a Role in Cigarette Smoke Addiction? Addiction Research & Theory, e-published 2011 July 19. 169.Rahman MN, Vlahakis JV, Vukomanovic D, Szarek WA, Nakatsu K and Jia Z. A “double-clamp” binding mode for human heme oxygenase-1 inhibition. PLoS ONE (In press). 170.Dragic Vukomanovic, Brian McLaughlin, Mona N. Rahman, Walter A.Szarek, James F. Brien, Zongchao Jia, and Kanji Nakatsu. Selective Activation of Heme Oxygenase-2 by Menadione. Can J Physiol Pharmacol (In Press).