Selective Estrogen Receptor Modulator (SERM) Lasofoxifene Forms Reactive Quinones Similar to Estradiol

Abstract

The bioactivation of both endogenous and equine estrogens to electrophilic quinoid metabolites has been postulated as a contributing factor in carcinogenic initiation and/or promotion in hormone sensitive tissues. Bearing structural resemblance to estrogens, extensive studies have shown that many selective estrogen receptor modulators (SERMs) are subject to similar bioactivation pathways. Lasofoxifene (LAS), a third generation SERM which has completed Phase III clinical trials for the prevention and treatment of osteoporosis, is currently approved in the European Union for this indication. Previously, Prakash et al. (Drug Metab. Dispos. 2008, 36, 1218-26) reported that similar to estradiol, two catechol regioisomers of LAS are formed as primary oxidative metabolites, accounting for roughly half of total LAS metabolism. However, the potential for further oxidation of these catechols to electrophilic o-quinones has not been reported. In the present study, LAS was synthesized and its oxidative metabolism investigated in vitro under various conditions. Incubation of LAS with tyrosinase, human liver microsomes, or rat liver microsomes in the presence of GSH as a trapping reagent resulted in formation of two mono-GSH and two di-GSH catechol conjugates which were characterized by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Similar conjugates were also detected in incubations with P450 3A4, P450 2D6, and P450 1B1 supersomes. Interestingly, these conjugates were also detected as major metabolites when compared to competing detoxification pathways such as glucuronidation and methylation. The 7-hydroxylasofoxifene (7-OHLAS) catechol regioisomer was also synthesized and oxidized either chemically or enzymatically to an o-quinone that was shown to form depurinating adducts with DNA. Collectively, these data show that analogous to estrogens, LAS is oxidized to catechols and o-quinones which could potentially contribute to in vivo toxicity for this SERM.

Tamoxifen Mimics the Effects of Endogenous Ovarian Hormones on Repeated Seizures Induced by Pentylenetetrazole in Rats

“…For example the maintenance of bone density and its cardio protective effects are examples of tamoxifen agonistic effects [17]. While, tamoxifen behaves as an antiestrogen in the breast tissue [18] and it also prevents of ovariectomy-induced downregulation of Bcl-2 and up-regulation of Bax expression [19]. In the central nervous system (CNS), tamoxifen was shown to reduce infarct size and neurobehavioral deficits due to middle cerebral artery occlusion in rats [20].…”

Selective estrogen receptor modulators: tissue specificity and clinical utility

“… 145 – 147 This SERM has been shown to function as a skeletal agonist and a breast and uterine antagonist. 44 , 148 – 152 Lasofoxifene’s structure is similar to that of endogenous estrogens, with a polyaromatic phenol scaffold that may be oxidized to catechols 153 which may cause toxicity. Lasofoxifene is a third generation nonsteroidal SERM with a similar structure to idoxifene.…”

The effects of tamoxifen and soy on dark neuron production in hippocampal formation after pentylenetetrazole-induced repeated seizures in rats

“…The maintenance of bone density and its cardio protective effects are examples of agonistic effects of tamoxifen [39]. While, it behaves as an antiestrogen in the breast tissue [40] and it also prevents of ovariectomy-induced downregulation of Bcl-2 and upregulation of Bax expression [41].…”