Croyle, Maria A., Ph.D.
Proposed Model for Regulation of CYP Expression in the Kidney After Systemic Administration of Recombinant Adenovirus. From Le et al. Hum. Gene Ther. (2006).
Effect of Adenovirus on the Pharmacokinetic Profile of Docetaxel From Wonganan et al. (2009) Cancer Gene Ther.
Representative Microarray Images Obtained from Liver Samples of Rats Treated with Recombinant Viral Vectors.
Diagrams of potential mechanisms by which adenoviral infection alters hepatic CYP3A2 in the rat.
Dose Response of AdlacZ on CYP3A2 Activity 48 Hours after Infection of Primary Hepatocytes
Representative Transgene Expression Levels in Cultured Hepatocyte Monolayers 48 Hours After Infection (from Piyanuch Wonganan)
Treatment with a RGD Peptide for 2 Hours Significantly Suppresses CYP CYP3A2 Activity in Primary Hepatocytes
Representative Kidney Sections Histochemically Stained for Beta-Galactosidase Expression 24 Hours After Virus Administration
Schematic Overview of the Regulation of the 5��� Flanking Region of the CYP3A4 Promoter by Specific Transcription Factors in the Liver. Taken from Croyle (2009) Expert Opin Drug Metab Toxicol. and created by Stephen Schafer.
A Single Dose of Active and Inactive Adenovirus Significantly Reduces Hepatic CYP3A2 Activity in the Male Sprague-Dawley Rat for 14 Days without Return to Baseline. Taken from Callahan et al. (2008) Virol. J.
Effect of Recombinant Viruses on Hepatic, Renal and Intestinal Drug Metabolism
Early clinical observations of changes in drug metabolism during infection sparked investigation in the role the immune response on the expression and function of the cytochrome P450 system. Of particular interest was a report in 1978 noting an increase in theophylline half life in patients during adenovirus infection (t1/2 686 min. during acute infection, t1/2 303 min. 1 month later, (Chang et al. Lancet. 1978 1(8074):1132-3)). Because recombinant adenovirus has a high affinity for the liver, it is often used clinically in patients that are ill and must be maintained on supportive medications or in combination with chemotherapeutic agents, and is capable of causing significant illness in several patient populations, study of the effect of this virus on drug metabolizing enzymes is important as significant alterations could result in drug-drug interactions, subtherapeutic or toxic drug levels.
Cytochromes P450 (CYP) are a superfamily of genes whose enzymes are responsible for the metabolism of many drugs, chemicals and endogenous compounds. We chose to study hepatic CYP isoforms 3A2 and 2C11 and renal CYP isoforms 4A1, 4A2 and 2E1 in the male Sprague Dawley rat, a common model for the assessment of drug metabolism of novel medicinal compounds. Hepatic CYP3A2 was selected because its human correlate, CYP3A4, is responsible for the metabolism of ~60% of medications currently on the market. Hepatic CYP2C11 does not have a human correlate, but is influenced by inflammatory mediators. Renal CYP 4A1, 4A2, and 2E1 each play a role in fatty acid homeostasis and arachidonic acid metabolism and play a role in the control of renal blood flow, platelet aggregation, inflammation and apoptosis.
Current studies focus on the mechanism by which virus infection alters CYP expression and function at the cellular level. Preliminary data suggests that engagement of certain cell surface receptors initiates changes in cell signal transduction pathways that alter factors responsible for CYP expression and function. Other physiological changes that occur during virus infection can also change CYP at the post-translational level as well.
Project Funding: Past and Present
UT Summer Research Assignment
UT VP for Research Special Research Grant
UT Undergraduate Research Fellowships
Croyle, M.A. 2009 Long-Term Virus-Induced Alterations of CYP3A-Mediated Drug Metabolism: A Look at the Virology, Immunology and Molecular Biology of a Multi-Faceted Problem Expert Opin Drug Metab Toxicol. 2009 5(10):1189-211.
Wonganan, P., Zamboni, W.C., Strychor, S., Dekker, J.D. and Croyle, M.A. Drug-Virus Interaction: Effect of Administration of Recombinant Adenoviruses on the Pharmacokinetics of Docetaxel in a Rat Model. 2009 Cancer Gene Therapy 16(5):405-14.
Callahan, S. M., Wonganan, P., and Croyle, M. A. Molecular and Macromolecular Alterations of Recombinant Adenoviral Vectors Do Not Resolve Changes in Hepatic Drug Metabolism During Infection. Viorlogy Journal 2008 Sept. 30 5:111 doi: 10.1186/1743-422X-5-111.
Boquet, M.P., Wonganan, P., Dekker, J.D., and Croyle, M.A. Impact of Route of Systemic Administration of Adenovirus on Virus-Mediated Toxicity: Focus on Mortality, Virus Distribution, and Drug Metabolism. J. Pharmacol. Toxicol. Methods . 2008 58(3):222-32.
Le, H. T., Boquet, M. P., Clark, E. A., Callahan, S. M., and Croyle, M. A. Renal Pathophysiology after Systemic Administration of Recombinant Adenovirus: Changes in Renal Cytochromes P450 Based upon Vector Dose. Hum. Gene Ther. 2006 17(11):1095-1111.
Callahan, S. M., Boquet, M. P., Ming, X., Brunner, L. J. and Croyle, M. A. Impact of Transgene Expression on Drug Metabolism Following Systemic Adenoviral Vector Administration. J. Gene Med. 2006 8(5):566-576.
Callahan, S. M., Ming, X., Lu, S. K., Brunner, L. J. and Croyle, M. A. Considerations for Use of Recombinant Adenoviral Vectors: Dose Effect on Hepatic Cytochromes P450. J. Pharmacol. Exp. Ther. 2005 312(2):492-501.
Recent Presentations at National and International Meetings
University of Houston, College of Pharmacy Department of Pharmacological and Pharmaceutical Sciences. Houston, Texas March 25, 2009. "Pharmacology and Toxicology of Highly Efficient Recombinant Adenovirus-Based Ebola Vaccines"
University of British Columbia Department of Pharmaceutical Sciences, Vancouver, B.C. October 16, 2007. Maria A. Croyle, invited speaker for departmental seminar. "Impact of A Single Dose of Recombinant Virus on Important Physiological Processes"
"Recent Advances and Prospects in the Development of Combined Biotechnology Drugs" Chosun University Gwangju, South Korea September 10-11, 2007. Maria A. Croyle, invited speaker. "Impact of Recombinant Viruses on Hepatic Drug Metabolism".
Pharmaceutical Sciences World Congress: Optimizing Drug Therapy- An Imperative for World Health. Amsterdam, The Netherlands. April 22-25, 2007.
Wonganan, P., Callahan. S.M. and Croyle M.A. A Single Dose of Recombinant Adenovirus Significantly Alters Hepatic and Renal Cytochrome P450 Expression and Function for 14 Days
Fifteenth Annual Meeting of the American Association of Pharmaceutical Scientists. San Antonio, TX. October 29 to November 2, 2006.
Wonganan, P., Callahan, S. M., and Croyle, M. A. Development of an In Vitro Model for Mechanistic Study of Adenovirus-Mediated Alterations in Hepatic Cytochromes P450
Eighth Annual Meeting American Association Of Gene Therapy, St. Louis, M.O. June 1-5, 2005.
Callahan, S. M., Boquet, M. P., Wonganan, P., and Croyle, M. A. Molecular and Macromolecular Alterations of Recombinant Adenoviral Vectors Do not Eliminate Changes in Hepatic Drug Metabolism
College of Pharmacy
The University of Texas
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Austin, TX, USA
Email Address: pharmacy
Dr. Bill Williams has been named editor-in-chief of AAPS PharmSciTech, the online research journal of the American Association of Pharmaceutical Scientists.