Brief Biography

Dr. Ito received his MD from Jichi Medical School, Japan, in 1979. He trained in Paediatrics, followed by a Clinical and Research Fellowship in Clinical Pharmacology in Toronto, and joined University of Toronto faculty in 1995. As a clinician-scientist, Ito focuses his research effort on breastfeeding pharmacology, ranging from molecular mechanisms of drug excretion into milk, to its pharmacokinetics and infant safety.

Clinical Care Activities

1. Diagnosis, prevention and management of severe and complicated adverse drug reactions in children and adults (consultation service, and a DART clinic)
2. Consultation for drug safety in pregnancy and lactation

Research Interests

1. Clinical safety of drugs in pregnancy and breastfeeding
2. Drug transport systems in the mammary gland and other tissues
3. Oxidative stress and drug transporting proteins
4. Effects of human milk on infant drug metabolyzing enzymes
5. Tonicity-regulation of human drug metabolizing enzymes

Research Activities

1. 1. Breastfeeding pharmacology. Focusing on drug safety in pregnant and breastfeeding women and their infants, I conduct patient-based studies to provide safety data to clinical practice.
      
   2. Transport of xenobiotics. My research program investigates drug transfer mechanisms of the mammary gland. Our focus will move to a new transporter gene we have cloned. In addition, we have recently begun examining transporter regulation mediated by NRF2 (a transcription factor to counteract oxidative stress). Using in vitro approaches and the Nrf2-knockout mice in vivo, our goal is to elucidate roles of Nrf2 in various diseases caused by oxidative stress [CIHR-funded].
      
   3. Effects of milk on development of detoxification mechanisms. This research program funded by CIHR has just begun to explore influences of human milk and its alternatives (i.e., formula) on development of cytochrome P450 enzymes and major drug transporters. The goal is to reveal biological importance of human milk to infants.
      
   4. Osmotic regulation of CYP3A. Cytochrome P450 3A (CYP3A) is one of the major drug metabolizing enzymes, and more than half of all drugs in the market are metabolized by this enzyme. We discovered that levels of this enzyme vary depending on tonicity of the cellular environment. Funded by CIHR, we are investigating how this enzyme is influenced by "tonicity", hoping that this novel mechanism has a key to full understanding of individual differences of the enzyme function.

Future Research Interests

The ultimate goal of my research program is to advance our knowledge base for better drug safety in children, especially in breastfed infants. To this end, we will continue exploring key biological functions of human milk on drug handling capability of infants, and the fundamental mechanisms of drug-induced toxicities. As a future focus, we plan to reveal the roles of the new transporter we have cloned.

External Funding

• CIHR [Drugs and Human Milk]
• CIHR [Novel transcriptional control of human cytochrome P450 3A]
• Genome Canada [Genotype-specific Approaches in Therapeutics in Children (site director)]
• PSI [Depression during breastfeeding]

Achievements

1997-2002 - The Career Award in Health Sciences (CIHR/Rx&D Health Research Foundation)

1996 - Piafsky Young Investigator Award from the Canadian Society for Clinical Pharmacology.

Publications

Tan KP, Yang M, Ito S. Activation of Nrf2 by toxic bile acids provokes adaptive defense responses to enhance cell survival at the emergence of oxidative stress. Mol Pharmacol 2007;72:1380-1390

Kosuge K, Chuang A, Uematsu S, Tan KP, Ko BCB, Ohashi K, Ito S. Discovery of osmo-sensitive transcriptional regulation of human cytochrome P450 3As by the tonicity-responsive enhancer binding protein (nuclear factor of activated T cells 5). Mol Pharmacol 2007;72:826-837

Kwok B, Yamauchi A, R. Rajesan, L. Chen, Dhillon U, Gao W. Xu H, Wang B, Takahashi S, Semple J, Tamai I, Nezu J, Tsuji A, Harper P, Ito S. Carnitine/xenobiotics transporters in the human mammary gland epithelia, MCF12A. Am J Physiol [Regul Integr Comp Physiol]. 2006;290:793-802.

Xu H, Rajesan R, Harper P, Kim RB, Lonnerdal B, Yang M, Uematsu S, Hutson J, Watson-MacDonell J, Ito S. Induction of cytochrome P450 1A by cow milk-based formula: a comparative study between human milk and formula. Br J Pharmacology 2005; 146; 296-305

Moretti ME, Sgro M, Johnson DW, Sauve RS, Woolgar MJ, Taddio A, Verjee Z, Giesbrecht E, Koren G, Ito S. Cyclosporine excretion into breast milk. Transplantation 2003; 75:2144-2146

Ito S, Alcorn J. Xenobiotics transporter expression and function in the human mammary gland. Adv Drug Deliv Rev 2003;55:653-655

Lala P, Ito S, Lingwood C. Retroviral transfection of MDCK cells with human MDR1 results in a major increase in globotriaosyl ceramide and increased cell sensitivity to verocytotoxin: role of P-glycoprotein in glycolipid synthesis. J Biol Chem 2000; 275:6246-6251.

Ito S. Drug therapy for breast-feeding women. New Engl J Med 2000; 343:118-126

Lee A, Moretti M, Collanties A, Chong D, Mazzotta P, Koren G, Marchant SS, Ito S. Choice of breastfeeding and physician's advice: a cohort study of women receiving propylthiouracil. Pediatrics 2000; 106:27-30.

Ito S, Woodland C, Sarkadi B, Hockman G, Walker S, Koren G. Modeling of P-glycoprotein-involved epithelial drug transport in MDCK cells. Am J Physiol 1999;277(1 Pt 2):F84-F96.