Pathway Aromatase Inhibitor Pathway (Multiple Tissues), Pharmacodynamics

Action of aromatase inhibitors in multiple tissues
Diagrammatic representation of the synthesis of estrogen in post-menopausal women and its blockade by aromatase inhibitors.
Aromatase Inhibitor Pathway (Multiple Tissues), Pharmacodynamics
hsd17b1 cyp19a1 hsd17b1 hsd17b1 cyp19a1 sts hsd17b1 sults sts sults hsd17b1 cyp19a1 sts sults cyp19a1 aromatase inhibitors aromatase inhibitors
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Description

Estrogen plays an important role in initiating and promoting breast cancer (reviewed in 1). This pathway shows the rate-limiting biosynthesis of estrogen from androgens by aromatase and its inhibition by aromatase inhibitors/inactivators in postmenopausal women. Aromatase, an enzyme of the cytochrome P450 (CYP450) subfamily and the product of the CYP19A1 gene, is highly expressed in the placenta and in the granulose cells of ovarian follicles in premenopausal women 2. Its expression depends on cyclical gonadotropin stimulation 3. In addition, aromatase is also present at lower levels in several nonglandular tissues that include subcutaneous fat, liver, muscle, brain, normal breast and breast cancer tissue 4. Estrogen production after menopause is solely from nonglandular sources, particularly subcutaneous fat. In menopause, androstenedione produced in the adrenals and, to a small extent, testosterone produced in the ovaries are released to the circulation and then sequestered to nonglandular tissues (e.g., liver and breast cells), where they are converted to estrone and estradiol, respectively, by aromatase located in these tissues 5. In the liver and in breast tissue, estrone and estradiol undergo oxidation by CYP450s to a number of hydroxylated metabolites 6. Estrone and estradiol in these tissues also undergo conjugation by sulfotransferases (SULTs) or deconjugation by steroid sulfatase (STS) 7. In all tissues, hydroxysteroid (17-beta) dehydrogenase (HSD17B) converts androstenedione to testosterone and estrone to estradiol 5.
Drugs that effectively inhibit the aromatase-mediated synthesis of estrogens in peripheral tissues including the breast, thus depriving the system of estrogens, are widely used in the treatment of breast cancer 4. These drugs include the nonsteroidal triazole derivatives anastrozole and letrozole and the steroidal exemestane.

Authors: Zeruesenay Desta, Anne Nguyen, David Flockhart, Todd Skaar, Rebecca Fletcher, Richard Weinshilboum, Dorit S. Berlin, Teri E. Klein, Russ B. Altman.
Citation:
Desta Zeruesenay, Nguyen Anne, Flockhart David, Skaar Todd, Fletcher Rebecca, Weinshilboum Richard, Berlin Dorit S, Klein Teri E, Altman Russ B. "Antiestrogen pathway (aromatase inhibitor)" Pharmacogenetics and genomics (2009).
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History:
Therapeutic Categories:
  • Anticancer agents

Entities in the Pathway

Genes (5)

Drugs/Drug Classes (1)

Relationships in the Pathway

Arrow FromArrow ToControllersPMID
androstenedione estrone CYP19A1 12700178, 19250199
androstenedione estrone CYP19A1
androstenedione testosterone HSD17B1 12700178
CYP19A1 CYP19A1 Enzyme inhibitors 11821457, 15939586, 9748124
CYP19A1 CYP19A1 Enzyme inhibitors 11821457, 15939586, 9748124
CYP19A1 CYP19A1 Enzyme inhibitors 11821457, 15939586, 9748124
CYP19A1 CYP19A1 Enzyme inhibitors 11821457, 15939586, 9748124
estradiol sulfate estradiol STS 14623544
estradiol estradiol sulfate SULT1A1, SULT1E1 10963623, 12922923, 15860265
estradiol estrone
estradiol estrone
estradiol estrone
estrone sulfate estrone STS 14623544
estrone sulfate estrone STS 14623544
estrone estradiol HSD17B1
estrone estradiol HSD17B1
estrone estradiol HSD17B1
estrone estrone sulfate SULT1A1, SULT1E1 10963623, 12922923, 15860265
estrone estrone sulfate SULT1A1, SULT1E1 10963623, 12922923, 15860265
testosterone androstenedione
testosterone estradiol CYP19A1 19250199
testosterone estradiol CYP19A1
androstenedione androstenedione
androstenedione androstenedione
androstenedione androstenedione
androstenedione androstenedione
androstenedione androstenedione
estradiol estradiol
estradiol estradiol
estrone estrone
estrone estrone
testosterone testosterone
testosterone testosterone
testosterone testosterone
testosterone testosterone
testosterone testosterone

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