A Potent and Selective Inhibitor of P450 1B1: Implications for Breast Cancer Treatment

F. Peter Guengerich
Vanderbilt University
P30ES00267

Background: Cytochrome P450s are a class of enzymes found primarily in the liver responsible for metabolism of a wide variety of innate and xenobiotic chemicals. Cytochrome P450 1B1 is unique in that it is found mainly found outside the liver in steroid producing tissues, such as the ovary, testis, and adrenal gland, and in a variety of human tumors. P450 1B1 metabolically activates the hormone 17ß-estradiol (E2) to 4-hydroxy E2. This conversion has been suggested as a step in some forms of breast cancer development.

Advance: These investigators examined the capacity of 2,4,3',5'-tetramethoxystilbene (TMS) to inhibit the activity of P450 1B1. TMS proved to be very effective in inhibiting the activity of the enzyme based on a number of different metabolic assays. It also was very selective for the 1B1 isozyme as compared to P450 1A1 and 1A2. Trapping agents such as glutathione, N-acetylcysteine, or dithiothreitol did not block the TMS-induced inhibition of P450 1B1.

Implication: These results suggest that TMS is a potent and selective inhibitor of P450 1B1. Other studies have shown that TMS itself is not mutagenic. Therefore, it warrants further investigation as a possible preventive agent for breast cancer formation by E2 in humans. TMS is also a useful compound for characterizing the enzymatic properties of P450 1B1 because of its strong selectivity among P450 enzymes.

Citation: Chun YJ, Kim S, Kim D, Lee SK, Guengerich FP. A new selective and potent inhibitor of human cytochrome P450 1B1 and its application to antimutagenesis. Cancer Res. 2001 Nov 15;61(22):8164-70.