QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: dmd.107.018960v1 36/5/963    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Rahman, M. Articles by Sutter, T. R. Search for Related Content PubMed PubMed Citation Articles by Rahman, M. Articles by Sutter, T. R.

CYP1B1 Is Not a Major Determinant of the Disposition of Aromatase Inhibitors in Epithelial Cells of Invasive Ductal Carcinoma

W. Harry Feinstone Center for Genomic Research (M.R., C.H.S., Q.T.T., G.L.S., T.R.S.) and Departments of Chemistry (M.R., G.L.E., T.R.S.) and Biology (M.R., C.H.S., Q.T.T., G.L.S., T.R.S.), University of Memphis, Memphis, Tennessee; Department of Pathology, General Hospital Graz West, Graz, Austria (S.F.L.); Fox Chase Cancer Center, Philadelphia, Pennsylvania (J.R.); and School of Medicine, University of Virginia, Charlottesville, Virginia (R.J.S.)

CYP1B1 and CYP19 (aromatase) have been shown to be expressed in breast tumors. Both enzymes are efficient estrogen hydroxylases, indicating the potential for overlapping substrate and inhibitor specificity. We measured the inhibition properties of aromatase inhibitors (AIs) against CYP1B1-catalyzed hydroxylation of 17β-estradiol (E2) to determine whether CYP1B1 affects the disposition of AIs. In addition, we estimated the frequency of coexpression of these enzymes in breast tumor epithelium. Immunohistochemical analyses of CYP19 and CYP1B1 in a panel of 29 cases of invasive ductal carcinoma of the breast showed epithelial cell staining for CYP19 in 76% and for CYP1B1 in 97% of the samples. Statistical analysis showed no significant correlation (0.33) for positive expression of CYP19 and CYP1B1 (p > 0.07). CYP1B1 inhibition was determined for two steroidal inhibitors: formestane and exemestane and five nonsteroidal inhibitors: aminoglutethimide, fadrozole, anastrozole, letrozole, and vorozole. Of the seven compounds tested, only vorozole exhibited inhibition of CYP1B1 activity with IC₅₀ values of 17 and 21 µM for 4-hydroxy estradiol and 2-hydroxy estradiol, respectively. The estimated K_i values of vorozole for E2 4- and 2-hydroxylation were 7.26 and 6.84 µM, respectively. Spectrophotometric studies showed that vorozole was a type II inhibitor of CYP1B1. This study shows that with the exception of vorozole, the aromatase inhibitors are selective for CYP19 relative to CYP1B1. Thus, although both CYP19 and CYP1B1 are expressed in a high percentage of breast cancers, CYP1B1 is not a major determinant of the disposition of AIs.