The Endogenous Selective Estrogen Receptor Modulator 27-Hydroxycholesterol Is a Negative Regulator of Bone Homeostasis

DuSell, Carolyn D.; Nelson, Erik R.; Wang, Xiaojuan; Abdo, Jennifer; Mödder, Ulrike I.; Umetani, Michihisa; Gesty‐Palmer, Diane; Javitt, Norman B.; Khosla, Sundeep; McDonnell, Donald P.

doi:10.1210/jcem.95.7.9983

Cited by 19 publications

(29 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Through action on liver X receptors, 27HC also increased breast tumor metastasis (Nelson et al, 2013). In bone, 27HC attenuated estrogen action and had negative effects on bone mineralization (DuSell et al, 2010). Epidemiologic and other studies support the role of 27HC as a SERM.…”

Section: Introductionmentioning

confidence: 82%

Marketed Drugs Can Inhibit Cytochrome P450 27A1, a Potential New Target for Breast Cancer Adjuvant Therapy

2015

View full text Add to dashboard Cite

Cytochrome P450 CYP27A1 is the only enzyme in humans converting cholesterol to 27-hydroxycholesterol, an oxysterol of multiple functions, including tissue-specific modulation of estrogen and liver X receptors. Both receptors seem to mediate adverse effects of 27-hydroxycholesterol in breast cancer when the levels of this oxysterol are elevated. The present work assessed druggability of CYP27A1 as a potential antibreast cancer target. We selected 26 anticancer and noncancer medications, most approved by the Food and Drug Administration, and evaluated them first in vitro for inhibition of purified recombinant CYP27A1 and binding to the enzyme active site. Six strong CYP27A1 inhibitors/binders were identified. These were the two antibreast cancer pharmaceuticals anastrozole and fadrozole, antiprostate cancer drug bicalutamide, sedative dexmedetomidine, and two antifungals ravuconazole and posaconazole. Anastrozole was then tested in vivo on mice, which received subcutaneous drug injections for 1 week. Mouse plasma and hepatic 27-hydroxycholesterol levels were decreased 2.6-and 1.6-fold, respectively, whereas plasma and hepatic cholesterol content remained unchanged. Thus, pharmacologic CYP27A1 inhibition is possible in the whole body and individual organs, but does not negatively affect cholesterol elimination. Our results enhance the potential of CYP27A1 as an antibreast cancer target, could be of importance for the interpretation of Femara versus Anastrozole Clinical Evaluation Trial, and bring attention to posaconazole as a potential complementary anti-breast cancer medication. More medications on the US market may have unanticipated off-target inhibition of CYP27A1, and we propose strategies for their identification.

show abstract

Section: Introductionmentioning

confidence: 82%

Marketed Drugs Can Inhibit Cytochrome P450 27A1, a Potential New Target for Breast Cancer Adjuvant Therapy

2015

View full text Add to dashboard Cite

show abstract

“…Binding of 27-hydroxycholesterol to ERa reduces bone density (DuSell et al, 2010;Nelson et al, 2011). The K d s of 27-hydroxycholesterol for ERa and ERb are about 1.3 and 0.4 mM, respectively (Umetani et al, 2007;, which is over 10 3 times higher than the K d of E2 for human ERa and ERb (Kuiper et al, 1997).…”

Section: -Hydroxycholesterolmentioning

confidence: 89%

“…The estrogenic activity of 5a-androstanediol in the brain (Zuloaga et al, 2012a,b) and prostate (Muthusamy et al, 2011;Weihua et al, 2002) of D 5 -androstenediol in brain microglia (Saijo et al, 2011), and 27-hydroxycholesterol in bone (DuSell et al, 2010;Nelson et al, 2011) and breast cancer cells Wu et al, 2013) has expanded our concept of ligands that are transcriptional regulators of ERa and ERb. Further studies with D 5 -androstenediol, 5a-androstanediol, and 27-hydroxycholesterol complexed with ERa and ERb in a variety of tissues during different stages in development may uncover additional physiological responses mediated by these 'alternative' estrogens.…”

Section: Future Researchmentioning

confidence: 99%

Estrogen Physiology from an Evolutionary Perspective

Baker

2014

Reference Module in Biomedical Sciences

View full text Add to dashboard Cite

“…Recently, Umetani et al [40] reported that several hydroxylated cholesterols including 27-hydroxycholesterol [27-OH-C], 22R-OH-C, 24S-OH-C and 25-OH-C bound human ER and human ER . 27-OH-C was the most potent, and in some mammalian cells 27-OH-C functions as a partial agonist for human ER and ER [40][41][42][43]. The Kd of 27-OH-C for ER and ER is about 1.3 M and 0.4 M, respectively [40][41][42], which is over 10 3 times higher than the Kd of E2 for human ER and ER [30,40].…”

Section: Was the Ancestral Estrogen A Cholesterol Analog?mentioning

confidence: 90%

Insights from the structure of estrogen receptor into the evolution of estrogens: Implications for endocrine disruption

Baker

2011

Biochemical Pharmacology

View full text Add to dashboard Cite

The Endogenous Selective Estrogen Receptor Modulator 27-Hydroxycholesterol Is a Negative Regulator of Bone Homeostasis

Cited by 19 publications

References 0 publications

Marketed Drugs Can Inhibit Cytochrome P450 27A1, a Potential New Target for Breast Cancer Adjuvant Therapy

Marketed Drugs Can Inhibit Cytochrome P450 27A1, a Potential New Target for Breast Cancer Adjuvant Therapy

Estrogen Physiology from an Evolutionary Perspective

Insights from the structure of estrogen receptor into the evolution of estrogens: Implications for endocrine disruption

Contact Info

Product

Resources

About