During her sophomore year, Asal Sadatrafiei became interested in applying what she was learning in the classroom to a hands-on situation and she started thinking about getting involved in research. She approached Dr. Blumberg about his interests and was soon working on several projects in his lab. Her passion for research grew as she found value in conducting successful experiments. Now completing her second year in the University of California, San Francisco Pharmacy program, Asal says her UCI research experiences were excellent preparation for her pharmaceutical studies because the subject of her research furthered understanding of the biological mechanisms of drug metabolism and drug-nutrient interactions.

For decades it has been known that vitamin supplements, including Vitamin E, affect drug metabolism. Vitamin E exists in eight isoforms: a-, b-, g-, d- tocopherol and a-, b-, g-, d- tocotrienol. All isoforms of Vitamin E are initially metabolized by w-oxidation, which is catalyzed by cytochrome P450 enzymes (CYP). The CYP family of isoenzymes is one of the major groups of drug metabolizing enzymes and is regulated by the steroid and xenobiotic receptor, SXR. We show here that the four tocotrienols, but not tocopherols, specifically bind to and activate SXR. Surprisingly, tocotrienols show tissue-specific induction of SXR target genes; in primary hepatocytes, tocotrienols are able to up-regulate expression of CYP3A4, but not UDP glucuronosyltransferase 1A1 (UGT1A1) or multidrug resistance protein-1 (MDR1) genes, whereas tocotrienols induce MDR1 and UGT1A1 but not CYP3A4 expression in intestinal LS180 cells. These findings provide a molecular mechanism to explain why vitamin supplements affect the absorption and effectiveness of drugs. Knowledge of drug-nutrient interactions may help reduce the incidence of decreased drug efficacy.

Bruce Blumberg School of  Biological Sciences

This work illustrates that vitamins may have unexpected effects on the absorption and effectiveness of drugs. Asal and her coworkers showed that tocotrienol forms of Vitamin E (commonly found in cereal grains) activate the steroid and xenobiotic receptor, SXR. This activation leads to increased expression of genes involved in drug and xenobiotic metabolism and could lead to decreased effectiveness of prescription drugs. Paradoxically, this effect is expected to be stronger with natural Vitamin E which contains both tocopherol and tocotrienol forms as compared to synthetic Vitamin E. Asal worked in my laboratory for more than two years and this experience whetted her interest in research. This research was particularly important in Asal’s choice of pharmaceutical research as her future field of study.