Comparative study of the short-term effects of a novel selective estrogen receptor modulator, ospemifene, and raloxifene and tamoxifen on rat uterus

Zheng, Huili; Kangas, Lauri; Härkönen, Pirkko

doi:10.1016/j.jsbmb.2003.11.009

Cited by 17 publications

(10 citation statements)

References 55 publications

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“…Upon further examination, the major metabolite in rats was found to be M1 (Lindstrom et al, 1984), similar to what we found for glucuronidation of raloxifene in Caco-2 cells (Jeong et al, 2004). Because many of the pharmacodynamic studies of raloxifene are conducted in rats (Merchenthaler et al, 1998;Kubatka et al, 2001;Cao et al, 2002;Ozgonul et al, 2003;Zheng et al, 2004), it would be important to resolve why there were these important species differences in raloxifene disposition. Therefore, the main purpose of the present study is to determine how species and disposition model choice affect the intestinal and hepatic disposition of raloxifene.…”

supporting

confidence: 74%

“…Preclinical studies exploring raloxifene's anticancer effects have used rodents (e.g., rats) as their primary model (Merchenthaler et al, 1998;Kubatka et al, 2001;Cao et al, 2002;Ozgonul et al, 2003;Zheng et al, 2004). Because of the substantial difference in the metabolism of raloxifene (e.g., 39% bioavailability in rats and 2% in humans), the results derived from rodents must be weighed carefully before extrapolating to humans.…”

Section: Discussionmentioning

confidence: 99%

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Species- And Disposition Model-Dependent Metabolism of Raloxifene in Gut and Liver: Role of Ugt1a10

Jeong¹,

Liu²,

Lin³

et al. 2005

Drug Metab Dispos

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ABSTRACT:Caco-2 cell lysate, and intestinal and liver microsomes derived from female humans and rats were used to compare and contrast the metabolism and disposition of raloxifene. In Caco-2 cell lysate, raloxifene 6-␤-glucuronide (M1) was the main metabolite, although raloxifene 4-␤-glucuronide (M2) was formed in comparable abundance (58% versus 42%). In rat liver and intestinal microsomes, M1 represented about 76 to 86% of glucuronidated metabolites. In contrast, raloxifene 4-␤-glucuronide (M2) was the predominant metabolite in expressed UGT1A10 (96%) and human intestinal (92%) microsomes. Intrinsic clearance for M2 (CL int, M2 ) in human intestinal microsomes was 33-to 72-fold higher than in rat microsomes, whereas intrinsic clearance for M1 (CL int, M1 ) was 3-to 4-fold lower. Taken together, total intrinsic clearance (CL int, M1 ؉ CL int, M2 ) in human intestinal microsomes was 3-to 6-fold higher than that in rat intestinal microsomes, but was similar in liver microsomes. In addition, intrinsic clearance in small intestinal microsomes was 2-to ϳ5-fold higher than that in hepatic microsomes, regardless of species. To account for the difference in species-and disposition model-dependent intestinal metabolism, we probed the presence of various UGT1A isoforms in Caco-2 cells using real-time reverse transcriptase-polymerase chain reaction and, as expected, detected no UGT1A10. In conclusion, the lack of UGT1A10 may explain why Caco-2 cell and rat intestinal microsomes metabolized raloxifene differently from human intestinal microsomes. The presence of human intestinal UGT1A10 and the higher overall intrinsic clearance value in the human intestine as the result of UGT1A10 expression could explain why raloxifene has much lower bioavailability in humans (2%) than in rats (39%).

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supporting

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Species- And Disposition Model-Dependent Metabolism of Raloxifene in Gut and Liver: Role of Ugt1a10

Jeong¹,

Liu²,

Lin³

et al. 2005

Drug Metab Dispos

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“…The duration of exposure to raloxifene as well as other estrogenic compounds is a critical determinant of activation of different mechanisms in reproductive tissues (Zheng et al, 2004). Therefore, short-term nongenomic effects of raloxifene as discussed above may be associated with long-term genomic effects in the vessel wall.…”

Section: Discussionmentioning

confidence: 99%

Raloxifene Elicits Combined Rapid Vasorelaxation and Long-Term Anti-Inflammatory Actions in Rat Aorta

Pinna

Bolego

Sanvito

et al. 2006

J Pharmacol Exp Ther

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Previous studies reported the ability of raloxifene to acutely relax arterial and venous vessels, but the underlying mechanisms are controversial. Anti-inflammatory effects of the drug have been reported in nonvascular tissues. Therefore, the aim of this study was to investigate the nature of short-and longterm effects of raloxifene on selected aspects of vascular function in rat aorta. Isometric tension changes in response to raloxifene were recorded in aortic rings from ovariectomized female rats that underwent estrogen replacement, whereas long-term experiments were performed in isolated aortic smooth muscle cells (SMCs). Raloxifene (0.1 pM-0.1 M) induced acute vasorelaxation through endothelium-and nitric oxide (NO)-dependent, prostanoid-independent mechanisms. The relaxant response to raloxifene was significantly weaker than that to 17␤-estradiol and was sensitive to neither the nonselective estrogen receptor antagonist ICI 182,780 [7,4,5,5,sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17-diol] nor a selective estrogen receptor (ER) ␣ antagonist. This rapid vasorelaxant effect was retained in aortic rings from rats treated with 0.1 mg/kg, but not 1 mg/kg, lipopolysaccharide, 4 h before sacrifice. In cultured aortic SMCs, raloxifene treatment (1 nM-1 M) for 24 h reduced inducible NO synthase activation in response to cytokines. This effect was prevented by the selective ER␣ antagonist and was associated with upregulation of ER␣ protein levels, which dropped markedly upon cytokine stimulation. These findings illustrate the relevance of classic ER-dependent pathways to the vascular anti-inflammatory effects rather than to the nongenomic vasorelaxation induced by raloxifene and may assist in the design of novel ER isoform-selective estrogen-receptor modulators targeted to the vascular system.Raloxifene is a selective estrogen-receptor modulator (SERM) approved for use in osteoporosis and has been suggested to be cardioprotective in women at high risk for coronary heart disease (Barrett-Connor et al., 2002), although these results were from post hoc analyses. In fact, the results of the recently completed RUTH (Raloxifene Use for The Heart) study indicate that treatment with raloxifene does not significantly affect the risk of coronary events in postmenopausal women at risk for coronary disease (Barrett-Connor et al., 2006). Thus, a more detailed understanding of raloxifene pharmacological action in vascular tissues is required to better define and unravel potential benefits of treatment with raloxifene and other SERMs.A certain number of studies have examined the direct effects of raloxifene on the vessel wall. It has been consistently shown that the drug acutely relaxes different arterial (Figtree et al., 1999;Tsang et al., 2004;Chan et al., 2005;Leung et al., 2005) and venous (Bracamonte et al., 2002;Chan et al., 2005) vessels from different animal species. A variety of underlying mechanisms, however, can be involved, including enhanced endothelial NO production (Figtree et al., 1999;Bracamonte et al., 200...

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“…O efeito proliferativo do estrogênio é parcialmente devido aos fatores de crescimento, como o fator insulinóide tipo I (IGF-I), epidérmico (EGF) e o vásculo-endotelial (VEGF) [19][20][21] . Outros estudos mostraram que o raloxifeno não aumenta a expressão do IGF-I 22 e EGF-I 23 . Contudo, pode estimular a expressão de VEGF no útero de ratas 20 .…”

Section: Discussão O Collaborative Group On Hormonal Factors In Breasunclassified

Efeitos da terapia estro-raloxifeno sobre o endométrio de ratas

Moraes

Simões

Fonzar

et al. 2006

Rev. Bras. Ginecol. Obstet.

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RESUMOObjetivo: avaliar os efeitos dos estrogênios conjugados eqüinos (Ece) e do raloxifeno (Ral), isoladamente ou associados, sobre o endométrio de ratas adultas. Métodos: foram utilizadas 56 ratas adultas, ooforectomizadas, divididas aleatoriamente em sete grupos: GCont (controle); GEce (Ece 50 μg/kg); GEce/25 (Ece 25 μg/kg); GRal/0,75 (Ral 0,75 mg/kg); GRal/0,4 (Ral 0,4 mg/kg); GEce-Ral (50/0,75) -(Ece 50 μg/kg + Ral 0,75 mg/kg) e GEce-Ral (25/0,4) -(Ece 25 μg/kg + Ral 0,4 mg/kg). As drogas foram administradas por gavagem durante 21 dias consecutivos. Ao final da administração todos os animais foram anestesiados e fragmentos dos úteros removidos, fixados em formol a 10% e processados para inclusão em parafina. Os cortes obtidos foram corados por HE e submetidos à avaliação histomorfométrica. Foram avaliados os seguintes parâmetros: espessura do epitélio superficial, número de glândulas endometriais/mm 2 e número de vasos sangüíneos presentes no miométrio/mm 2 . Os dados obtidos foram submetidos a análise estatística de ANOVA seguida pelo teste de Tukey-Kramer. Resultados: nos grupos controle (Gcont) e tratados isoladamente com raloxifeno (GRal/0,75 e GRal/0,4) o endométrio mostrou-se atrófico. Já nos grupos tratados com Ece isoladamente foi observado endométrio muito desenvolvido, sendo este efeito mais acentuado no grupo que recebeu 50 μg/kg, no qual encontramos aumento da espessura do epitélio superficial e da lâmina própria e no número de glândulas endometriais e de vasos sanguíneos. Notamos também proliferação endometrial nos grupos que receberam a associação de Ece e Ral (GEce-Ral -50/0,75) e (GEce-Ral -25/0,4). Conclusão: o raloxifeno parece bloquear parcialmente a ação do estrogênio no endométrio de ratas adultas castradas. PALAVRAS-CHAVE:Raloxifeno; Estrogênios; Terapia de reposição hormonal; Endométrio ABSTRACT Purpose: to evaluate the effects of conjugated equine estrogens (CEE) and raloxifene (Ral), alone or combined, on the rat endometrium. Methods: fifty-six adult rats were ovariectomized and randomly divided into seven groups: GCont (control); GCEE (CEE 50 μg/kg); GCEE/25 (CEE 25 μg/kg); GRal/0.75 (Ral 0.75 mg/kg); GRal/0.4 (Ral 0.4 mg/kg); GCEE-Ral (50/0.75) -(CEE 50 μg/kg + Ral 0.75 mg/kg), and GCEE-Ral (25/0.4) -(CEE 25 μg/kg + Ral 0.4 mg/kg). The drugs were orally administered (gavage) for 21 consecutive days. At the end of the experiment, all animals were anesthetized and sacrificed. Fragments of uterus were removed, fixed in 10% formaldehyde and processed for paraffin inclusion. The histological sections were stained by HE and submitted to histomorphometric evaluation. The following parameters were analyzed: thickness of superficial epithelium and number of endometrial glands/mm 2 and of blood vessels/mm 2 . The data were evaluated using ANOVA followed by the Turkey-Kramer test. Results: in the GCont and only Ral treatment (GRal/0.75 and GRal/0.4) the endometrium showed signals of atrophy. In the groups treated with only CEE signs of endometrial proliferation were observed, mainly in group...

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Comparative study of the short-term effects of a novel selective estrogen receptor modulator, ospemifene, and raloxifene and tamoxifen on rat uterus

Cited by 17 publications

References 55 publications

Species- And Disposition Model-Dependent Metabolism of Raloxifene in Gut and Liver: Role of Ugt1a10

Species- And Disposition Model-Dependent Metabolism of Raloxifene in Gut and Liver: Role of Ugt1a10

Raloxifene Elicits Combined Rapid Vasorelaxation and Long-Term Anti-Inflammatory Actions in Rat Aorta

Efeitos da terapia estro-raloxifeno sobre o endométrio de ratas

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