Aromatase is localized in the endoplasmic reticulum where it is regulated by tissue-specific promoters that are in turn controlled by hormones, cytokines, and other factors. It catalyzes the last steps of estrogen biosynthesis from androgens (specifically, it transforms androstenedione to estrone and testosterone to estradiol). These steps include three successive hydroxylations of the 19-methyl group of androgens, followed by simultaneous elimination of the methyl group as formate and aromatization of the A-ring.
General reaction for the conversion of testosterone to estradiol catalyzed by aromatase. Steroids are composed of four fused rings (labeled A-D). Aromatase converts the ring labeled "A" into an aromatic state.
The gene expresses two transcript variants.[2] In humans, the gene CYP19, located on chromosome 15q21.1, encodes the aromatase enzyme.[3] The gene has nine coding exons and a number of alternative non-coding first exons that regulate tissue specific expression.[4]
Aromatase is generally highly present during the differentiation of ovaries.[6][7] It is also susceptible to environmental influences, particularly temperature. In species with temperature-dependent sex determination, aromatase is expressed in higher quantities at temperatures that yield female offspring.[6] Despite the fact that data suggest temperature controls aromatase quantities, other studies have shown that aromatase can overpower the effects of temperature: if exposed to more aromatase at a male-producing temperature, the organism will develop female and conversely, if exposed to less aromatase at female-producing temperatures, the organism will develop male (see sex reversal).[6] In organisms that develop through genetic sex determination, temperature does not affect aromatase expression and function, suggesting that aromatase is the target molecule for temperature during TSD[6] (for challenges to this argument, see temperature-dependent sex determination). It varies from species to species whether it is the aromatase protein that has different activity at different temperatures or whether the amount of transcription undergone by the aromatase gene is what is temperature-sensitive, but in either case, differential development is observed at different temperatures.[8]
Role in neuroprotection
Aromatase in the brain is usually only expressed in neurons. However, following penetrative brain injury of both mice and zebra finches, it has been shown to be expressed in astrocytes.[9] Furthermore, it has also been shown to decrease apoptosis following brain injury in zebra finches.[10] This is thought to be due to the neuroprotective actions of estrogens, including estradiol. Research has found that two pro-inflammatory cytokines, interleukin-1β (IL-1β) and interleukin-6 (IL-6), are responsible for the induction of aromatase expression in astrocytes following penetrative brain injury in the zebra finch.[11]
A number of investigators have reported on a rather rare syndrome of excess aromatase activity. In boys, it can lead to gynecomastia, and in girls to precocious puberty and gigantomastia. In both sexes, early epiphyseal closure leads to short stature. This condition is due to mutations in the CYP19A1 gene which encodes aromatase.[12] It is inherited in an autosomal dominant fashion.[13] It has been suggested that the pharaoh Akhenaten and other members of his family may have suffered from this disorder,[14] but more recent genetic tests suggest otherwise.[15] It is one of the causes of familial precocious puberty—a condition first described in 1937.[16]
This syndrome is due to a mutation of gene CYP19 and inherited in an autosomal recessive way. Accumulations of androgens during pregnancy may lead to virilization of a female at birth (males are not affected). Females will have primary amenorrhea. Individuals of both sexes will be tall, as lack of estrogen does not bring the epiphyseal lines to closure.
Inhibition of aromatase
The inhibition of aromatase can cause hypoestrogenism (low estrogen levels). The following natural products have been found to have inhibiting effects on aromatase.
↑Vaz ADN (2003). "Chapter 1: Cytochrome activation by cytochromes P450: a role for multiple oxidants in the oxidation of substrates". In Fisher, Michael; Lee, Jae Kyu; Obach, Robert E. Drug metabolizing enzymes: cytochrome P450 and other enzymes in drug discovery and development. Lausanne, Switzerland: FontisMedia SA. ISBN0-8247-4293-1.
↑Toda K, Shizuta Y (April 1993). "Molecular cloning of a cDNA showing alternative splicing of the 5'-untranslated sequence of mRNA for human aromatase P-450". Eur. J. Biochem. 213 (1): 383–9. doi:10.1111/j.1432-1033.1993.tb17772.x. PMID8477708.
↑Czajka-Oraniec I, Simpson ER (2010). "Aromatase research and its clinical significance". Endokrynol Pol. 61 (1): 126–34. PMID20205115.
↑Gasnier C, Dumont C, Benachour N, Clair E, Chagnon MC, Séralini GE (2009). "Glyphosate-based herbicides are toxic and endocrine disruptors in human cell lines". Toxicology. 262 (3): 184–91. doi:10.1016/j.tox.2009.06.006. PMID19539684.
↑ 6.06.16.26.3Duffy TA, Picha ME, Won ET, Borski RJ, McElroy AE, Conover DO (August 2010). "Ontogenesis of gonadal aromatase gene expression in atlantic silverside (Menidia menidia) populations with genetic and temperature-dependent sex determination". J Exp Zool A Ecol Genet Physiol. 313 (7): 421–31. doi:10.1002/jez.612. PMID20623799.
↑Fukami M, Shozu M, Soneda S, Kato F, Inagaki A, Takagi H, Hanaki K, Kanzaki S, Ohyama K, Sano T, Nishigaki T, Yokoya S, Binder G, Horikawa R, Ogata T (June 2011). "Aromatase excess syndrome: identification of cryptic duplications and deletions leading to gain of function of CYP19A1 and assessment of phenotypic determinants". J. Clin. Endocrinol. Metab. 96 (6): E1035–43. doi:10.1210/jc.2011-0145. PMID21470988.
↑Braverman IM, Redford DB, Mackowiak PA (April 2009). "Akhenaten and the strange physiques of Egypt's 18th dynasty". Annals of Internal Medicine. 150 (8): 556–60. doi:10.7326/0003-4819-150-8-200904210-00010. PMID19380856.
↑Ziora K, Oświecimska J, Geisler G, Broll-Waśka K, Szalecki M, Dyduch A (2006). "[Familial precocious puberty -- a variant of norm or pathology?]". Endokrynol Diabetol Chor Przemiany Materii Wieku Rozw (in Polish). 12 (1): 53–8. PMID16704862.CS1 maint: Unrecognized language (link)
↑Satoh K, Sakamoto Y, Ogata A, Nagai F, Mikuriya H, Numazawa M, Yamada K, Aoki N (2002). "Inhibition of aromatase activity by green tea extract catechins and their endocrinological effects of oral administration in rats". Food and Chemical Toxicology. 40 (7): 925–33. doi:10.1016/S0278-6915(02)00066-2. PMID12065214.
↑Kapiszewska M, Miskiewicz M, Ellison PT, Thune I, Jasienska G (2006). "High tea consumption diminishes salivary 17β-estradiol concentration in Polish women". British Journal of Nutrition. 95 (5): 989–95. doi:10.1079/BJN20061755. PMID16611391.
↑Le Bail JC, Pouget C, Fagnere C, Basly JP, Chulia AJ, Habrioux G (2001). "Chalcones are potent inhibitors of aromatase and 17β-hydroxysteroid dehydrogenase activities". Life Sciences. 68 (7): 751–61. doi:10.1016/S0024-3205(00)00974-7. PMID11205867.
↑Siler U, Barella L, Spitzer V, Schnorr J, Lein M, Goralczyk R, Wertz K (2004). "Lycopene and Vitamin E interfere with autocrine/paracrine loops in the Dunning prostate cancer model". FASEB J.18 (9): 1019–21. doi:10.1096/fj.03-1116fje. PMID15084515.
↑Ye L, Chan FL, Chen S, Leung LK. "The citrus flavonone hesperetin inhibits growth of aromatase-expressing MCF-7 tumor in ovariectomized athymic mice". J Nutr Biochem. 23: 1230–7. doi:10.1016/j.jnutbio.2011.07.003. PMID22209285.
↑Chen S, Oh SR, Phung S, Hur G, Ye JJ, Kwok SL, Shrode GE, Belury M, Adams LS, Williams D (December 2006). "Anti-aromatase activity of phytochemicals in white button mushrooms (Agaricus bisporus)". Cancer Res. 66 (24): 12026–34. doi:10.1158/0008-5472.CAN-06-2206. PMID17178902.
Attar E, Bulun SE (May 2006). "Aromatase inhibitors: the next generation of therapeutics for endometriosis?". Fertil. Steril. 85 (5): 1307–18. doi:10.1016/j.fertnstert.2005.09.064. PMID16647373.
Strobel HW, Thompson CM, Antonovic L (2001). "Cytochromes P450 in brain: function and significance". Curr. Drug Metab. 2 (2): 199–214. doi:10.2174/1389200013338577. PMID11469726.
Bulun SE, Yang S, Fang Z, Gurates B, Tamura M, Zhou J, Sebastian S (2002). "Role of aromatase in endometrial disease". J. Steroid Biochem. Mol. Biol. 79 (1–5): 19–25. doi:10.1016/S0960-0760(01)00134-0. PMID11850203.
Balthazart J, Baillien M, Ball GF (2002). "Phosphorylation processes mediate rapid changes of brain aromatase activity". J. Steroid Biochem. Mol. Biol. 79 (1–5): 261–77. doi:10.1016/S0960-0760(01)00143-1. PMID11850233.
Richards JA, Petrel TA, Brueggemeier RW (2002). "Signaling pathways regulating aromatase and cyclooxygenases in normal and malignant breast cells". J. Steroid Biochem. Mol. Biol. 80 (2): 203–12. doi:10.1016/S0960-0760(01)00187-X. PMID11897504.
Balthazart J, Baillien M, Ball GF (2002). "Interactions between aromatase (estrogen synthase) and dopamine in the control of male sexual behavior in quail". Comp. Biochem. Physiol. B, Biochem. Mol. Biol. 132 (1): 37–55. doi:10.1016/S1096-4959(01)00531-0. PMID11997208.
Meinhardt U, Mullis PE (2002). "The aromatase cytochrome P-450 and its clinical impact". Horm. Res. 57 (5–6): 145–52. doi:10.1159/000058374. PMID12053085.
Meinhardt U, Mullis PE (2003). "The essential role of the aromatase/p450arom". Semin. Reprod. Med. 20 (3): 277–84. doi:10.1055/s-2002-35374. PMID12428207.
Carreau S, Bourguiba S, Lambard S, Galeraud-Denis I (2003). "[Testicular aromatase]". J. Soc. Biol. 196 (3): 241–4. PMID12462076.
Carani C, Fabbi M, Zirilli L, Sgarbi I (2003). "[Estrogen resistance and aromatase deficiency in humans]". J. Soc. Biol. 196 (3): 245–8. PMID12462077.
Simpson ER (2004). "Biology of aromatase in the mammary gland". Journal of Mammary Gland Biology and Neoplasia. 5 (3): 251–8. doi:10.1023/A:1009590626450. PMID14973387.
Bulun SE, Takayama K, Suzuki T, Sasano H, Yilmaz B, Sebastian S (2004). "Organization of the human aromatase p450 (CYP19) gene". Semin. Reprod. Med. 22 (1): 5–9. doi:10.1055/s-2004-823022. PMID15083376.
Simpson ER (2004). "Aromatase: biologic relevance of tissue-specific expression". Semin. Reprod. Med. 22 (1): 11–23. doi:10.1055/s-2004-823023. PMID15083377.
Bulun SE, Fang Z, Imir G, Gurates B, Tamura M, Yilmaz B, Langoi D, Amin S, Yang S, Deb S (2004). "Aromatase and endometriosis". Semin. Reprod. Med. 22 (1): 45–50. doi:10.1055/s-2004-823026. PMID15083380.
Shozu M, Murakami K, Inoue M (2004). "Aromatase and leiomyoma of the uterus". Semin. Reprod. Med. 22 (1): 51–60. doi:10.1055/s-2004-823027. PMID15083381.
Chen S, Ye J, Kijima I, Kinoshita Y, Zhou D (2005). "Positive and negative transcriptional regulation of aromatase expression in human breast cancer tissue". J. Steroid Biochem. Mol. Biol. 95 (1–5): 17–23. doi:10.1016/j.jsbmb.2005.04.002. PMID15955695.
Lambard S, Silandre D, Delalande C, Denis-Galeraud I, Bourguiba S, Carreau S (2005). "Aromatase in testis: expression and role in male reproduction". J. Steroid Biochem. Mol. Biol. 95 (1–5): 63–9. doi:10.1016/j.jsbmb.2005.04.020. PMID16019206.
Bulun SE, Imir G, Utsunomiya H, Thung S, Gurates B, Tamura M, Lin Z (2005). "Aromatase in endometriosis and uterine leiomyomata". J. Steroid Biochem. Mol. Biol. 95 (1–5): 57–62. doi:10.1016/j.jsbmb.2005.04.012. PMID16024248.
Ellem SJ, Risbridger GP (2006). "Aromatase and prostate cancer". Minerva Endocrinol. 31 (1): 1–12. PMID16498360.
Brueggemeier RW, Díaz-Cruz ES (2006). "Relationship between aromatase and cyclooxygenases in breast cancer: potential for new therapeutic approaches". Minerva Endocrinol. 31 (1): 13–26. PMID16498361.
Jongen VH, Hollema H, Van Der Zee AG, Heineman MJ (2006). "Aromatase in the context of breast and endometrial cancer. A review". Minerva Endocrinol. 31 (1): 47–60. PMID16498363.
Hiltunen M, Iivonen S, Soininen H (2006). "Aromatase enzyme and Alzheimer's disease". Minerva Endocrinol. 31 (1): 61–73. PMID16498364.