Deanna
L. Kroetz, Ph.D.
Professor of
Biopharmaceutical Sciences and Pharmaceutical Chemistry

Contact Information:
deanna.kroetz@ucsf.edu
1550 4th Street
Room RH-584E
Box 2911
San Francisco, CA
94143-2911
Tel: (415) 476-1159
Fax: (415) 514-4361


Links:
Clinical Pharmacology
Pharmacogenetics

Publications

 

Antiretroviral and anti-cancer pharmacogenomics

Variability in response and toxicity associated with drug therapy of cancer and HIV/AIDS is a significant barrier to successful treatment of these diseases. The Kroetz laboratory studies the role of membrane transporters and drug metabolizing enzymes in determining the exposure of target cells to drugs. We are particularly focused on the multidrug resistance membrane transporters which are efflux pumps that export a large number of chemotherapeutic agents out of the cell. Laboratory based studies examine the effect of coding, promoter and UTR polymorphisms on transporter expression and function. Model cellular systems for drug toxicity, for example mitochondrial toxicity of antiretrovirals, are used to understand how transporters modulate toxicity and to determine whether polymorphisms in transporter genes alter this relationship. Clinical studies in cancer are conducted through the Cancer and Leukemia Group B (CALGB) cooperative and include pharmacogenetic studies in breast cancer and AML. In HIV, we are using a genome-wide approach to identify the genetic determinants of the immune response to therapy and antiretroviral associated toxicities in a resource-limited setting in Uganda.

Molecular regulation of cytochrome P450-catalyzed eicosanoid formation

A long-standing project in Dr. Kroetz's laboratory focuses on the generation of biologically active eicosanoids by cytochrome P450-mediated metabolism of arachidonic acid. These eicosanoids have potent effects on the renal vasculature and renal tubular ion transport and are implicated in the regulation of renal function and blood pressure. More recently they have been shown to play a role in inflammation. Our current work is focused on the anti-inflammatory properties of epoxyeicosatrienoic acids (EETs), a major cytochrome P450 eicosanoid produced in many tissues in response to phospholipase A2 activation. Selective and potent inhibitors of soluble epoxide hydrolase (sEH) and sEH knockout mice are used to modulate intracellular levels of EETs. Current mouse models being studied include TNFa-induced systemic inflammation and acute renal damage induced by cisplatin or ureter ligation. The signaling involved in the anti-inflammatory effects of EETs is examined both in vivo and in cellular systems. Parallel collaborative studies are being conducted to determine the significance of polymorphisms in the cytochrome P450 eicosanoid pathway on blood pressure and inflammation. The long term goal of this project is to identify novel therapeutic approaches to the treatment of inflammation.