Rosita Rodriguez Proteau EducationUniversity of Texas at Austin, BS Pharmacy, 1991, Ph.D., 1996 Dr. Proteau's research focuses on the development of in vitro cellular models to explore and evaluate the mechanism by which xenobiotics damage or injure specific cell types of various organs or tissues. Dr. Proteau works with primary culture systems of liver, heart, and skin as experimental models to study the cellular and subcellular toxicity of selected xenobiotics using sensitive indices of cytotoxicity. Her current research projects involve studies on ketoconazole's bioactivation and the elucidation of the mechanism(s) of ketoconazole-induced hepatotoxicity. Also, drug transport studies are being conducted utilizing intestinal cell cultures. Drug Toxicity StudiesThe mechanism(s) of ketoconazole induced hepatotoxicity is being investigated by evaluating the metabolism of ketoconazole using an in vivo model to provide a scientific and mechanistic basis for the hepatotoxicity documented in the clinical literature. Presently, mechanism(s) of toxicity or bioactivation of the azole antifungal agents has not been investigated in vivo. Covalent binding studies, toxicity studies, and metabolism studies are being performed. This project will provide an understanding of the metabolic pathway and hepatotoxic cellular mechanisms of ketoconazole. The results from this study will determine whether the toxicity of ketoconazole is attributed to the parent compound itself and/or the reactive metabolites in vivo. These studies were being supported by the 1999 Research Starter Grant from the Pharmaceutical Research and Manufacturers of America Foundation, Inc. Drug Transport and M etabolism Studies We are developing in vitro model systems to evaluate "first-pass" effect which evaluate intestinal drug metabolism as well as liver metabolism. The models will predict drug "absorption windows" as well as drug absorption kinetics and drug metabolism kinetics. Elucidation of the molecular interactions between the various transport processes of drugs from gastrointestinal tissue is also being investigated in attempt to facilitate drug absorption and drug delivery to the various regions of the GI tract (stomach, duodenum, ileum, jejunum, colon, and rectum). These novel applications of the in vitro "first-pass" effect model will predict drug absorption, gut wall metabolism, liver metabolism, overall bioavailability, "first-pass" metabolism of the drug, and intestinal drug metabolism kinetics.
Awards and Other Professional Activities2005 - 2006 Chair, Education Committee for the Society of Toxicology, SOT. 2005 - 2006 President, Pacific Northwest Association of Toxicologist (PANWAT), SOT's Regional Chapter 2004 - present Associate Member, Environmental Health Sciences Center 2004 - present Affilated Member, Center for Gene Research and Biotechnology 2004 - 2005 Vice-President, PANWAT, SOT's Regional Chapter 2004 - 2005 Chair, Subcommittee of Minority Initiatives (SCMI) for SOT 2003 - present Referee, Toxicology Letters 2003 - present Referee, Drug Metabolism and Disposition 2003 - 2004 Co-Chair, SOT's SCMI committee 2003 - 2006 Member, Education Committee for SOT 2003 - 2004 Vice-President Elect, PANWAT 2003 - 2005 Councilor, SOT's In Vitro Specialty Section 2002 - 2003 Member, Program Development Committee for NIDDK's , Network of Minority Research Investigators (NMRI) 2002 - 2006 Director, T-35 NIEHS Training Grant for Minority Undergraduate Research, Environmental Health Sciences (EHS) Center at OSU 2002 - present Associate Professor of Pharmaceutics College of Pharmacy 2002 - 2003 Chairperson, Continuing Education Committee for SOT 2000 - 2003 Member, Continuing Education Committee for SOT 2000 - 2002 Chairperson, Membership Committee for SOT's In Vitro Specialty Section 2000 Referee, the Science of the Total Environment 1999 - present Adjunct Faculty, Environmental and Molecular Toxicology at OSU 1999 - 2000 Recipient of Pharmaceutical Research & Manufacturers of America Foundation Starter Grant 1999 - present Featured scientist at Oregon Museum of Science and Industry, Portland, OR 1997 - present NIEHS Training Grant Faculty, EHS at OSU 1997 - 2003 Referee, Molecular Pharmacology 1996 - present Member, Editorial Advisory Board for Toxicology In Vitro 1996 - 2002 Assistant Professor of Pharmaceutics College of Pharmacy 1995 - present Referee, Toxicology In Vitro
Professional AffiliationsRho Chi Pharmaceutical Honor Society, International Society for the Study of Xenobiotics, Society of Toxicology, American Association of Pharmaceutical Scientists, American Association of Colleges of PharmacyPublicationsFan, Y. and Rodriguez-Proteau. "Berberine and berbamine modulate P-glycoprotein" submitted, 2009. J.-S. Taur and R. Rodriguez-Proteau. "Effects of Dietary Flavonoids on the Transport of Cimetidine via P-glycoprotein and Cationic Transporters in Caco-2 and LLC-PK1 Cell Models " Xenobiotica, 38: 1536 - 1550. 2008. Fan, Y. and Rodriguez-Proteau. "Effects of ketoconazole on multidrug resistant-mediated transport in Caco-2 and MDCK-MDR1 drug transport models" Xenobiotica, 38: 107 - 129. 2008. Mata, J. E., Dyal, L. A., Slauson, M. E., Summerton, J., Loehr, C. ,Tyson, A. R., Rodriguez-Proteau, R., and Gustafson, S. "Tumor imaging using technetium-99m bound to pH sensitive peptides. Nanomedicine: Nanotechnology, Biology, and Medicine. 3: 297, 2007 . von Borstel Smith, M., Crofoot, K., Rodriguez-Proteau, R., and Filtz, T.M. "Effects of phenytoin and carbamazepine on calcium transport in Caco-2 cells." Toxicol. in Vitro, 21: 855, 2007. Rodriguez-Proteau, R., Mata, J. E., Miranda, C. L., Fan, Y., Brown, J. J., and Buhler, D. R. "Plant Polyphenols and Multi-Drug Resistance: Effects of Dietary Flavonoids on Drug Transporters in Caco-2 and MDCK-MDR1 cell transport models" Xenobiotica, 36: 41-58. 2006. Reprint version (PDF file) Mahadevan, B., Mata, J. E., Albershardt, D. J., Stevens, J. F., Pereira, C. B., Rodriguez-Proteau, R., W. M. Baird."The effects of red raspberry extract on PAH transport across Calu-3 cell monolayer, an in vitro cell model" International Journal Cancer Prevention,2: 129 - 141. 2005. Rodriguez-Proteau, R. and R. L. Grant "Toxicity Evaluation and Human Risk Assessment of Surface and Ground Water Contaminated by Recycled Hazardous Waste Materials" In: The Handbook of Environmental Chemistry: Vol. 5 Water Pollution: Environmental Impact Assessment of Recycled Hazardous Waste Materials on Surface and Ground Waters, Vol. Eds. T.A. Kassim and K. Williamson, Springer-Verlag, in pages 533 - 589 (2005). Blatt, D. H., Pryor, W. A., Mata, J. E., and R. Rodriguez-Proteau. "Re-evaluation of the relative potency of synthetic and natural alpha-tocopherol: Experimental observations and clinical trials" J. Nutritional Biochemistry15: 380 - 395, 2004. Reprint version (PDF file) Mata, J. E., Chen, Y., Gray, J. E., Williams, D. E., and R. Rodriguez-Proteau. "Effects of chlorophyllin on transport of dibenzo(a,1)pyrene, 2-amino-1-methyl-6-phenylimidazo-[4,5-b]pyridine, and aflatoxin B1 across Caco-2 cell monolayers." Toxicology 196: 117 - 125, 2004. Reprint version (PDF file) Rodriguez, R.J. and C. J. Buckholz "Hepatotoxicity of ketoconazole in Sprague Dawley rats: glutathione depletion, flavin-containing monooxygenases-mediated bioactivation, and hepatic covalent binding" Xenobiotica 33: 429- 442, 2003. Reprint version (PDF file) Grant, R. L., R.J. Rodriguez, C. S. Hofelt, and L. C. Haws "Shortcomings in USEPA approach for predicting risk due to consumption of animal food products impacted by air emissions from hazardous waste combustion facilities: a case study involving phthalates" Human Ecological Risk Assessment 8:1137 - 1154, 2002. Rodriguez, R.J., C.L. Miranda, J.F. Stevens, M.L. Deinzer, and D.R. Buhler. "Influence of prenylated and non-prenylated flavonoids on liver microsomal lipid peroxidation and oxidative injury in rat hepatocytes" Food Chemical Toxicology 39: 437 - 445, 2001. Rodriguez, R. J. and D. Acosta. Chapter 66: "Cardiac Toxicology" In: Heart Physiology and Pathophysiology, Eds. N. Sperelakis, Y. Kurachi, A. Terzic, and M. Cohen. Fourth Edition, pp. 1211 - 1224, Academic Press, CA (2001).
Rodriguez, R. J. and C.L. Miranda. "Isoform Specificity of N-Deacetyl Ketoconazole by Human and Rabbit Flavin-Containing Monooxygenases" Drug Metab. Dispos. 28: 1083 - 1086 (9) 2000.Reprint version (PDF file) Rodriguez, R. J., P.J. Proteau, B. L. Marquez, C.L. Hetherington, C.J. Buckholz, and K.L. O'Connell. "Flavin-containing monooxygenase-mediated metabolism of N-deacetyl ketoconazole by rat hepatic microsomes." Drug Metab. Dispos. 27: 880 - 886 1999. Reprint version (PDF file) Miranda, C.L., J.F. Stevens, A. Helmrich, M.C. Henderson, R.J.
Rodriguez, Y. Yea-Huey, M.L. Deinzer, D.W. Barnes, and D.R. Buhler.
"Antiproliferative and cytotoxic effects of prenylated flavonoids
from HOPS (Humulus Lupulus) in human cancer cell lines." Food Chem.
Toxicol. 37: 271 - 285, 1999. Abstract
Davila, J.C., R.J. Rodriguez, R.B. Melchert, and D. Acosta. "Predictive value of in vitro model systems in toxicology." Annual Review Pharmacol. Toxicol. 38:63-96, 1998 . Reprint version (PDF file) Rodriguez, R.J. and D. Acosta. "Metabolism of ketoconazole and N-deacetyl ketoconazole by rat hepatic microsomes and flavin-containing monooxygenases." Drug Metab. Dispos. 25:772-777, 1997. Reprint version (PDF file) Rodriguez, R.J. and D. Acosta. "N-deacetyl ketoconazole-induced hepatotoxicity in a primary culture system of rat hepatocytes." Toxicology 117:123-131, 1997 . Reprint version (PDF file) Rodriguez, R.J. and D. Acosta. "Inhibition of mitochondrial function in isolated rat liver mitochondria by azole antifungals." J. Biochem. Toxicol. 11:127-131, 1996 . Reprint version (PDF file) Rodriguez, R.J., J.C. Davila, and D. Acosta. "Establishment of flavin-containing monooxygenases in hepatic microsomes obtained from primary cultures of rat hepatocytes." Toxicologist 30:1215, 1996. Rodriguez, R.J. and D. Acosta. "Comparison of ketoconazole- and fluconazole-induced hepatotoxicity in a primary culture system of rat hepatocytes." Toxicology 96:83-92, 1995 . Reprint version (PDF file) Smith, P.C., W.Q. Song, and R.J. Rodriguez. "Covalent binding of etodolac acyl glucuronide to albumin in vitro." Drug Metab. Dispos. 63:221-223, 1992. Poster or Podium PresentationsFan, Y. and Rodriguez-Proteau, R. Effects of ketoconazole on multidrug resistant-mediated transport in Caco-2 and MDCKII-MDR1 drug transport models. Toxicological Sciences, The Toxicologist, 80 (1-S), Abstract #1686. Society of Toxicology Annual Meeting, San Diego, CA, 2006. Brown, J. J. and Rodriguez-Proteau, R. Effects of epigallocatechin gallate (EGCG), epicatechin gallate (ECG), and their derivatives on multidrug resistance (MRP)-mediated transport in Caco-2 and MDCKII-MDR1 drug transport models. Pacific Northwest Association of Toxicologist's 2005 regional meeting, September 8 - 9th, Astoria, OR 2005 Fan, Y. and Rodriguez-Proteau, R. Effects of ketoconazole, xanthohumol and epigallocatechin gallate on multidrug resistant-mediated transport in Caco-2 and MDCKII-MDR1 drug transport models. Pacific Northwest Association of Toxicologist's 2005 regional meeting, September 8 - 9th, Astoria, OR 2005 Dagadu, D. and Rodriguez-Proteau, R. Effects of chronic exposure to epicatechin gallate and epigallocatechin gallate on permeability of digoxin and cyclosporin-A in the Caco-2 drug transport model. Oregon State University, Department of Environmental and Molecular Toxicology, Corvallis, OR, 2005. Mata, J. E., Gustafson, S., Rodriguez-Proteau, R., Stauson, M., and Summerton, J. Nanoprobe directed tumor imaging using pH activated peptides as constrast agent carriers. Fourth Annual Era of Hope Department of Defense Breast Cancer Research Program Meeting, June 8-11, Philadelphia, PA 2005. Mata, J. E., Gustafson, S., Loehr, C., Rodriguez-Proteau, R., Slauson, M., Summerton, J. Tumor targeting using pH activated molecular engines. Eleventh Annual Blood-Brain Barrier Disruption Consortium Meeting. Nanobiology and Nanomedicine in the Pacific Northwest, Portland, OR, 2005. Mahadevan, B., Mata, J. E., Albershardt, D. J., Stevens, J. F., Pereira, C. B., Rodriguez-Proteau, R., W. M. Baird. Characterization of flavonoids in red raspberry extracts and their effects on carcinogen transport across Calu-3 cell monolayer. AACR's National Meeting, Anaheim, CA 2005. Mata, J. E., Miranda, C L., Buhler,D. R., Brown, J., and Rodriguez-Proteau, R. Effects of flavonoid treatment on the permeability of cyclosporin A across Caco-2 cell monolayers. Toxicological Sciences Society of Toxicology's National Meeting, Baltimore, MD 2004. Rodriguez, A. J., Tilton, S. C., Mata, J. E., Chen, J-L., Hall, K P., Williams, D E. and Rodriguez-Proteau, R. Transport characteristics of 3,3¹-diindolymethane using human dervied intestinal cells, CACO-2 and P27.7 cells. Toxicological Sciences Society of Toxicology's National Meeting, Baltimore, MD 2004. Mata , J. E., Yu, Z., Gray, J. E., Williams, D. E. and Rodriguez, R. J. Effects of chlorophyllin on transport of dibenzo[a,l] pyrene, 2-amino-1-methyl-6-phenylimidazo-[4,5-b]pyridine, and aflatoxin B1 across Caco-2 cell monolayers, Toxicological Sciences Society of Toxicology's National Meeting, Salt Lake City, Utah, 2003. Gray, J. E. and R. J. Rodriguez. The effect of chlorophyllin on the transport of aflatoxin B1, dibenzo[a,1]pyrene, phenylimidazo[4,5-b]pyridine in Caco-2 cells. Oregon State University, Department of Environmental and Molecular Toxicology, Corvallis, OR, 2002. Taur, J.-S. and R. J. Rodriguez. The effect of flavonoids on the permeability of cimetidine in Caco-2 cells. AAPS PharmSci Supplement, American Association of Pharmaceutical Scientists' National meeting, Toronto, Canada, November 2002. Rodriguez, R.J., J-S. Taur, D. Leibelt, and D.E. Williams. Complexation of dibenzo[A,L] pyrene (DBP) with chlorophyllin (CHL) reduces absorption across Caco-2 cell monolayers. International Congress of Toxicology meeting. Brisbane, Australia. 2001. Buckholz, C. J., S. Kimpau, and R. J. Rodriguez. Hepatic glutathione depletion in rats treated with ketoconazole. Toxicological Sci,60: 800, 2001 . Kimpau, S. and R. J. Rodriguez. In vivo toxicity evaluation of rats dosed with ketoconazole. Oregon State University, Department of Environmental and Molecular Toxicology, Corvallis, OR, 2000. Miller, J. D., R. J. Rodriguez, S. Y. Chang, T. Sakuma, C. Lu, and A. P. Li. Characterization of N-deacetylated ketoconazole metabolites produced by a recombinant human FMO system using triple quadrupole and QqTOF instruments. American Society of Mass Spectroscopy, Long Beach, CA, 2000. Buckholz, C. J. and Rodriguez, R. J. Covalent binding of ketoconazole in rat hepatic tissue. Toxicological Sci, 54 (1): 45, 2000. Kingkeohoi, S., Rodriguez, R. J., Filtz, T. M., and Miranda, C. L. Expression of flavin-containing monooxygenases in human intestine. Toxicological Sci, 54 (1): 47 - 48, 2000. Taur, J.-S., and Rodriguez, R. J. Flavonoid's effect on ketoconazole's bioavailability by human intestinal epithelial Caco-2 cells. AAPS PharmSci Supplement, 2580, 1999. Wilson, M. R. and Rodriguez, R. J. Isoform specificity of N-deacetyl ketoconazole by human and rabbit flavin-containing monooxygenases (FMO) and its mutagenic potential. Oregon State University, Department of Environmental and Molecular Toxicology, Corvallis, OR , 1999. Hetherington, F. L. and Rodriguez, R. J. Metabolism of N-deacetyl ketoconazole with recombinant human FMO1, FMO3, and FMO5. Apprenticeships in Science and Engineering, Saturday Academy Symposium, Portland, OR, 1999. Rodriguez, R. J., Miranda, C. L., Kingkeohoi, S., Stevens, J. F., Deinzer, M. L., and Buhler, D. R. Antioxidant and antihepatotoxic activities of prenylated flavonoids from HOPS. Toxicological Sci, 48 (1S): 197, 1999. O'Connell, K. L. and Rodriguez, R. J. Isolation, purification, and identification of N-deacetyl ketoconazole's metabolites. Apprenticeships in Science and Engineering, Saturday Academy Symposium at Portland State University, Portland, OR, 1998. Miranda, C. L., Stevens, J. F., Sharps, A., Henderson, M. C., Rodriguez, R. J., Deinzer, M. L. and Buhler, D. R. Cytotoxic effects of HOPS flavonoids on human cancer cells and on cultured rat hepatocytes. Toxicological Sci., 32: 185, 1998. Rodriguez, R. J. and Hetherington, C. L. Metabolism of N-deacetyl ketoconazole by adult rat hepatic microsomes. Toxicological Sci., 32: 284, 1998. Hetherington, C. L. and Rodriguez, R. J. Metabolism of ketoconazole and N-deacetyl ketoconazole by rat hepatic microsomes. Apprenticeships in Science and Engineering, Saturday Academy Symposium at Oregon State University, Corvallis, OR, 1997. Rodriguez, R. J., Davila, J. C., and Acosta, D. Establishment of flavin-containing monooxygenases in hepatic microsomes obtained from primary cultures of rat hepatocytes. Fund. Appl. Toxicol., 30: 1215, 1996. Rodriguez, R. J., Ziegler, D. M., and Acosta, D. Metabolism of ketoconazole and N-deacetyl ketoconazole by hepatic microsomes and flavin-containing monooxygenases. Pharmaceutical Research, 12: S383, 1995. Rodriguez, R. J. and Acosta, D. The effect of ketoconazole on metabolic integrity in relation to its cytotoxicity in cultured rat hepatocytes. Toxicologist, 15: 281, 1995. Rodriguez, R. J. and Acosta, D. Comparison of the cytotoxicity of fluconazole and ketoconazole using primary cell cultures of rat hepatocytes. Toxicologist, 14: 102, 1994. Rodriguez, R. J. and Acosta, D. Evaluation of the cytotoxicity of ketoconazole in primary cultures of rat hepatocytes. Toxicologist, 13: 340, 1993. Rodriguez, R. J., Song, W. Q. and Smith, P. C. Covalent binding of etodolac acyl glucuronide to human serum albumin in vitro. FASEB J., 5: a1210, 1991.
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