TY - JOUR
T1 - Bioactivation of the selective estrogen receptor modulator desmethylated arzoxifene to quinoids
T2 - 4′-fluoro substitution prevents quinoid formation
AU - Liu, Hong
AU - Liu, Ju
AU - Van Breemen, Richard B.
AU - Thatcher, Gregory R.J.
AU - Bolton, Judy L.
PY - 2005/2
Y1 - 2005/2
N2 - Although selective estrogen receptor modulators (SERMs) are useful in the treatment and prevention of breast cancer, the SERM tamoxifen has been associated with an increased risk of endometrial cancer possibly due to metabolism to electrophilic quinoids. Another SERM, arzoxifene is currently in clinical trials for the treatment of breast cancer, and since it has similar structural characteristics to tamoxifen, it also has the potential to form quinoids. In the current study, the active form of arzoxifene in vivo, desmethylated arzoxifene (DMA), was synthesized and chemically or enzymatically oxidized to DMA diquinone methide. The half-life of DMA diquinone methide at physiological pH and temperature was approximately 15 s. Reaction of DMA diquinone methide with glutathione (GSH) gave four mono-GSH conjugates, two di-GSH conjugates, and one tri-GSH conjugate. In incubations of DMA with GSH and either rat or human liver microsomes, DMA o-quinone-GSH conjugates were detected in addition to DMA diquinone methide-GSH conjugates. A DMA diquinone methide-deoxyguanosine adduct was detected following the incubation of DMA diquinone methide with deoxynucleosides. In preliminary studies with a human breast cancer cell line, DMA induced dose-dependent DNA damage and was more effective at causing DNA damage than raloxifene. These results suggest that DMA can be metabolized to electrophilic/redox-active quinoids, which have the potential to cause toxicity in vivo. A new fluorinated derivative unable to form a diquinone methide, 4′-F-DMA, was synthesized. 4′-F-DMA showed similar estrogen receptor (ER) binding affinity as compared to DMA. The antiestrogenic activity as measured by inhibition of estradiol-mediated induction of alkaline phosphatase activity in Ishikawa cells showed 10-fold lower activity for 4′-F-DMA compared to DMA; however, the antiestrogenic activity was comparable to raloxifene. In microsomal incubations of 4′-F-DMA in the presence of GSH, no GSH adducts were detected. These data suggest that 4′-F-DMA might be a promising SERM with similar activity to DMA and raloxifene and less toxicity.
AB - Although selective estrogen receptor modulators (SERMs) are useful in the treatment and prevention of breast cancer, the SERM tamoxifen has been associated with an increased risk of endometrial cancer possibly due to metabolism to electrophilic quinoids. Another SERM, arzoxifene is currently in clinical trials for the treatment of breast cancer, and since it has similar structural characteristics to tamoxifen, it also has the potential to form quinoids. In the current study, the active form of arzoxifene in vivo, desmethylated arzoxifene (DMA), was synthesized and chemically or enzymatically oxidized to DMA diquinone methide. The half-life of DMA diquinone methide at physiological pH and temperature was approximately 15 s. Reaction of DMA diquinone methide with glutathione (GSH) gave four mono-GSH conjugates, two di-GSH conjugates, and one tri-GSH conjugate. In incubations of DMA with GSH and either rat or human liver microsomes, DMA o-quinone-GSH conjugates were detected in addition to DMA diquinone methide-GSH conjugates. A DMA diquinone methide-deoxyguanosine adduct was detected following the incubation of DMA diquinone methide with deoxynucleosides. In preliminary studies with a human breast cancer cell line, DMA induced dose-dependent DNA damage and was more effective at causing DNA damage than raloxifene. These results suggest that DMA can be metabolized to electrophilic/redox-active quinoids, which have the potential to cause toxicity in vivo. A new fluorinated derivative unable to form a diquinone methide, 4′-F-DMA, was synthesized. 4′-F-DMA showed similar estrogen receptor (ER) binding affinity as compared to DMA. The antiestrogenic activity as measured by inhibition of estradiol-mediated induction of alkaline phosphatase activity in Ishikawa cells showed 10-fold lower activity for 4′-F-DMA compared to DMA; however, the antiestrogenic activity was comparable to raloxifene. In microsomal incubations of 4′-F-DMA in the presence of GSH, no GSH adducts were detected. These data suggest that 4′-F-DMA might be a promising SERM with similar activity to DMA and raloxifene and less toxicity.
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U2 - 10.1021/tx049776u
DO - 10.1021/tx049776u
M3 - Article
C2 - 15720120
AN - SCOPUS:13844269367
SN - 0893-228X
VL - 18
SP - 162
EP - 173
JO - Chemical Research in Toxicology
JF - Chemical Research in Toxicology
IS - 2
ER -