"I'm not one of those people who always knew she wanted to be a scientist," Deanna Kroetz says.

Kroetz was licensed as a pharmacist in Ohio in 1985, but today she is immersed in research projects encompassing a search for variant transporters causing drug resistance in ethnically diverse populations, pharmacology studies on genetically manipulated cells, clinical trials with breast cancer patients, and basic genetics research with brewer's yeast.

While she was studying pharmacy at Ohio State, a brief stint in a research laboratory began to turn Kroetz's head toward science. After graduate work at the University of Washington, where she gained experience in drug metabolism research -- and in un-Midwestern pursuits such as scuba diving -- followed by a postdoctoral fellowship at the National Institutes of Health, Kroetz came to UCSF in 1993, where today she is an associate professor of biopharmaceutical sciences.

While time devoted to science and family have sharply curtailed her outdoor adventures, her research horizons have continued to expand.

A major emphasis for Kroetz now is pharmacogenetics, the study of how people vary in their responses to drug treatments due to genetic differences. Understanding such differences can lead to screening tests that are useful in preventing individuals from being prescribed medications and dosages that are ineffective or harmful.

Kroetz is focusing on identifying variations in just a couple of genes, but the outcome of her work may affect the prescription of many classes of drugs, including protease inhibitors for HIV, chemotherapy for cancer, and nearly any drug with the potential to cause side effects in the central nervous system. The genes in question provide the blueprint for making protein "transporters." Cells use them to show the door to unwanted guests -- foreign molecules called "xenobiotics" -- and to encourage them to exit. "It's one way that our bodies get rid of things that are not supposed to be there," she says.

The transporters appear to have evolved to protect us from xenobiotics that we consume in our diets, but modern humans also take in xenobiotics as drugs. The transporters appear on cell membranes where protection is most needed: the barriers between blood and brain and between blood and testes, as well as in the placenta, where transporters help protect the fetus. Transporters are also present in the kidney and liver, organs that play a major role in the elimination of xenobiotics from the body.

Because the brain carries out so many important tasks, infiltration with relatively few xenobiotic molecules can quickly result in a noticeable impairment. Thanks in part to a large population of transporter proteins, the blood-brain barrier protects the central nervous system from drug doses that in most cases would be neurotoxic if the barrier were less effective, Kroetz says. A neurotoxic side effect experienced by millions, Kroetz notes, is the drowsiness caused by earlier generations of antihistamines.

Of course, sometimes it is desirable to get drugs into the brain, to treat depression, for example. Drug candidates to treat depression are screened to make sure they are not one of the many targets for common transporters.

Transporters do not export every foreign molecule. They are specific, but not too specific. Each type will transport many different molecules. "The reason that transporters have broad substrate specificity is that we don't get exposed to just a single toxic compound in our diets," Kroetz says. "We get exposed to groups of compounds.

"The most common transporter protein in the brain is P-glycoprotein, encoded for by a gene called MDR1 (multiple drug resistance gene 1). MDR1, and another common transporter gene, MRP (multiple drug resistance associated protein), are at the center of Kroetz's pharmacogenetics studies. The two transporters act on different groups of xenobiotics, with some overlap, and they are distributed differently in tissue and on cell membranes.

Using data from DNA samples from the National Institutes of Health, and also DNA samples obtained under the direction of UCSF physician and geneticist Esteban Gonzáles Burchard, Kroetz and colleagues have so far looked at about 500 chromosomes -- a matched pair from about 250 individuals -- and found 20 rare mutations in MDR1, as well as 28 more that they observed in more than one individual.

"We're looking at more individuals and more ethnically diverse populations than are being studied by most other researchers in the field," Kroetz says. "This gives us a much better feel for genetic diversity."

Some of the genetic variants Kroetz and colleagues have identified change the amino acid composition and structure of the encoded P-glycoprotein. Kroetz's research team is incorporating versions of these genes into mammalian cells grown in the lab, to see how the altered transporter proteins might function differently. Based on the results of these studies, Kroetz will decide which of the genetic variants to focus on in clinical studies.

Soon Kroetz will be heading the pharmacogenetics component of a large multicenter breast cancer trial. Women in whom breast tumors already have been surgically removed and who have chosen to take "adjuvant" chemotherapy to lessen the likelihood that cancer will return will be monitored to learn how inborn genetic variations in transporter genes might affect survival. Cells in many breast tumors are known to resist chemotherapy by evicting drugs through P-glycoprotein.

Kroetz also is collaborating with UCSF surgical oncologist Robert Warren, examining samples from tissue specimens obtained from patients with liver and colon cancer to see if different versions of MDR1 or MRP genes in normal cells are associated with survival or metastasis.

While she intends to strengthen her ties to clinical researchers at UCSF's Parnassus and Mt. Zion sites, Kroetz also looks forward to moving. "For me, going to Mission Bay is a great opportunity," she says. "I am a pharmacologist, but I have an interest in human genetics, and we will be surrounded by people trained in human genetics.