Rajgopal Govindarajan, Ph.D. Assistant Professor Pharmaceutical and Biomedical Sciences Office: Room 359 Phone: 706-542-5759 E-mail: rgovinda@rx.uga.edu

Biosketch

DVM (B.V.Sc)	Madras Veterinary College	Chennai, India	1991-1997
Ph.D. (Biochem & Mol Biol)	Univ. of Nebraska Med. Center	Omaha, NE	2000-2005
Postdoc (Drug Transport)	Univ. of Washington	Seattle, WA	2005-2008
Assistant Professor	Univ. of Georgia	Athens, GA	2008-present

Honors and Awards
Podium Presentation Award, AAPS Workshop on Drug Transporters-2007
Presidential Fellowship, University of Nebraska System, 2004-2005
Norm and Bernice Harris Award for Outstanding Work in Cancer Research during Graduate Studies,
University of Nebraska Medical Center & Eppley Cancer Center, 2003

Research Interests
Drug transporters are proteins that allow drugs to enter cells or, in some cases, act to keep them out. Because they are expressed in multiple tissues in the body, they play important roles in governing drug disposition. By directing drugs to specific cellular and subcellular domains, drug transporters could also play a crucial role in determining drug efficacy and toxicity. Hence, understanding the spatial, temporal, and functional regulation of drug transporters could provide a better insight into the pharmacological action of drugs. The importance of such studies is exemplified through narrow therapeutic-index drugs and those used in multi-drug regimen, as the resulting toxicities often hamper courses of treatment. Understanding the role of drug transporters could provide opportunities to modulate their function or modify the time, duration, combination or sequence of drugs administration to achieve more favorable therapeutic outcomes.

Currently, my laboratory focuses on the following:

a. One of the primary goals is to understand how drug transporters modulate tumor cell sensitivity or resistance to various nucleoside analogs (e.g. gemcitabine). More specifically, we are trying to understand how the nucleoside transporters, a key determinant of permeation of anti-cancer nucleoside drugs into cells, are regulated, both temporally and spatially, during normal cell cycle and during tumor progression. Further, we are investigating how drugs used in combination chemotherapy (e.g. paclitaxel) affect the functionality of nucleoside transporters and nucleoside drug sensitivity in cancer cells. Through these studies, we seek to identify optimal and effective strategies of using anti-cancer agents against solid tumor cell proliferation.

b. Another one of our active interests is investigating the toxicity of anti-HIV dideoxynucleosides (e.g. zidovudine; AZT). Although dideoxynucleosides are a cornerstone of highly active anti-retroviral therapy for patients with HIV-1 infection, their long-term use results in life-threatening mitochondrial toxicity manifested in various forms such as hepatitis, myopathy, peripheral neuropathy, lactacidosis and pancreatitis. Our recent studies have shown that certain nucleoside transporters (e.g. hENT3) expressed in the mitochondria are capable of directing anti-viral drugs into the mitochondria where they can get phosphorylated and incorporated into mitochondrial DNA. In furthering these studies, we are now investigating the molecular events of anti-HIV ddNs-induced mitochondrial toxicities with a goal of identifying ways to circumvent or minimize such toxicities.

c. Recently, we have also begun studies on a multi-specific group of transporters called organic anion transporting peptides (OATPs). OATPs transport a number of endogenous compounds (e.g. steroid hormones) and xenobiotics including statins. Statins are commonly used as the most effective medications for managing elevated low-density lipoprotein cholesterol levels. However, in certain patients, statins bring adverse cellular reactions in skeletal muscle that warrant discontinuation of medications. Using structure-function analyses and high-resolution imaging, we are intending to characterize single nucleotide polymorphisms in OATPs that can trigger statin induced myotoxicity.

Representative Publications
Veltkamp SA, Pluim D, van Eijndhoven MA, Bolijn MJ, Ong FH, Govindarajan R et al. (2008) New insights into the pharmacology, distribution, and cytotoxicity of gemcitabine and 2’,2’-difluorodeoxyuridine, Mol Cancer Ther., 7(8):2415-25

Govindarajan R, Endres CJ, Whittington D, LeCluyse E, Pastor-Anglada M, Tse CM and Unadkat JD (2008), Expression and hepato-biliary transport characteristics of equilibrative and concentrative nucleoside drug transporters in sandwich-cultured human hepatocytes, Am J Physiol Gastrointest Liver Physiol., 295(3):G570-80

Govindarajan R, Bakkhen AH, Hudkins KL, Lai Y, Tse CM, Casado FJ, Pastor-Anglada M and Unadkat JD (2007), In situ hybridization and immunohistochemical localization of concentrative and equilibrative nucleoside drug transporters in the human intestine, liver, kidneys and the placenta, Am J Physiol Reg Integ Comp Physiol. Vol. 293:R1809-1802

Rao PS, Govindarajan R, Mallya K and Rao US (2005) Characterization of a new antibody raised against the NH3-termius of P-glycoprotein, Clin. Can. Res., 15; 11 (16):5833-9.

Govindarajan R, et al. (2002) Impaired trafficking of connexins in Androgen-independent human prostate cancer cell lines and it’s mitigation by α-Catenin. J Biol. Chem., 277, (51), 50087- 50097.