CYP1B1 is not a major determinant of the disposition of aromatase inhibitors in epithelial cells of invasive ductal carcinoma.
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 17beta-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 IC(50) values of 17 and 21 microM 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 microM, 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.
Rahman
Mostafizur
M
W. Harry Feinstone Center for Genomic Research, University of Memphis, 201 Life Sciences Building, Memphis, TN 38152, USA.
Lax
Sigurd F
SF
Sutter
Carrie H
CH
Tran
Quynh T
QT
Stevens
Gaylene L
GL
Emmert
Gary L
GL
Russo
Jose
J
Santen
Richard J
RJ
Sutter
Thomas R
TR
D000818:Animals; D000906:Antibodies / Q000378:metabolism; D001141:Aromatase / Q000378:metabolism*; D047072:Aromatase Inhibitors / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases; D001943:Breast Neoplasms / Q000378:metabolism*; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism*; D065633:Cytochrome P-450 CYP1B1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D008297:Male; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D011817:Rabbits
D000906:Antibodies; D047072:Aromatase Inhibitors; D003577:Cytochrome P-450 Enzyme System; D001141:Aromatase; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D065633:Cytochrome P-450 CYP1B1