o-Quinone forming estrogens and selective estrogen receptor modulators (SERMs) have been associated with carcinogenesis. Long-term usage of tamoxifen has been associated with an increased risk of endometrial cancer. One potential mechanism of tamoxifen induced carcinogenesis involves metabolism to highly reactive carbocation intermediate, which could cause DNA damage through the formation of DNA adducts. In the present study, the potential for LY2066948 and lasofoxifene (LAS), to form electrophilic/redox active intermediates were investigated. In addition, the bioactivation of estrogens also explored for comparison in this study. LY2066948, a novel SERM in development by Eli Lilly for the treatment of uterine fibroids or myomas, has structural similarity to the equine estrogen equilenin present in hormone replacement formulations; both contain a naphthol group susceptible to oxidative metabolism to o-quinones. In model reactions with tyrosinase, the catechol metabolites of LY2066948 and equilenin were products; interestingly, in the presence of ascorbate to inhibit autoxidation, these catechols were formed quantitatively. Tyrosinase incubations in the presence of GSH gave the expected GSH conjugates resulting from trapping of the o-quinones, which were characterized by LC-MS/MS. Incubations of LY2066948 or equilenin with rat liver microsomes also gave detectable o-quinone trapped GSH conjugates; however, as observed with other SERMs, oxidative metabolism of LY2066948 mainly occurred on the amino side chain to yield the N-dealkylated metabolite. These studies suggest that although the naphthol group is susceptible to oxidative metabolism to long-lived o-quinones, the formation of these quinones by P450 can be attenuated by the chemistry of the remainder of the molecule as in the case of LY2066948. LAS is a third generation SERM, which has completed phase III clinical trials for osteoporosis prevention and treatment. However, since LAS has a polyaromatic phenol scaffold similar to endogenous estrogens, it has been hypothesized that LAS can form reactive quinoid metabolites. In this study, LAS was synthesized as a racemic mixture and its oxidative metabolism was investigated using various oxidative enzymes. Incubation of LAS with tyrosinase or rat liver microsomes in the presence of GSH gave two mono-GSH and two di-GSH conjugates, formed from trapping of the o-quinones. In addition, o-quinones GSH conjugates of LAS were also detected from the incubation of CYP3A4, CYP2D6 and CYP1B1 supersomes. These data show that, like endogenous estrogens, LAS is oxidized to catechols and o-quinones which could potentially cause toxicity in vivo.