Aromatase islocalized in theendoplasmic reticulum where it is regulated by tissue-specificpromoters that are in turn controlled byhormones,cytokines, and other factors. It catalyzes the last steps of estrogen biosynthesis from androgens (specifically, it transformsandrostenedione toestrone andtestosterone toestradiol). These steps include three successivehydroxylations of the 19-methyl group of androgens, followed by simultaneous elimination of the methyl group asformate and aromatization of the A-ring.
General reaction for the conversion oftestosterone toestradiol catalyzed by aromatase. Steroids are composed of four fusedrings (labeled A-D). Aromatase converts the ring labeled "A" into anaromatic state.
The gene expresses two transcript variants.[7] In humans, thegene CYP19, located onchromosome 15q21.1, encodes aromatase.[8] The gene has nine codingexons and a number of alternative non-coding first exons that regulate tissue specific expression.[9]
Aromatase is generally highly present during the differentiation of ovaries.[11][12] It is also susceptible to environmental influences, particularly temperature. In species withtemperature-dependent sex determination, aromatase is expressed in higher quantities at temperatures that yield female offspring.[11] 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 (seesex reversal).[11] 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[11] (for challenges to this argument, seetemperature-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.[13]
Aromatase in the brain is usually only expressed inneurons. However, following penetrative brain injury of both mice andzebra finches, it has been shown to be expressed inastrocytes.[14] It has also been shown to decreaseapoptosis following brain injury in zebra finches.[15] This is thought to be due to theneuroprotective actions of estrogens, including estradiol. Research has found that twopro-inflammatory cytokines,interleukin-1β (IL-1β) andinterleukin-6 (IL-6), are responsible for the induction of aromatase expression in astrocytes following penetrative brain injury in the zebra finch.[16]
A number of investigators have reported on a rather rare syndrome of excess aromatase activity. In boys, it createsgynecomastia, and in girls,precocious puberty andgigantomastia. In both sexes, earlyepiphyseal closure leads to short stature. This condition is due to mutations in the CYP19A1 gene which encodes aromatase.[17] It is inherited in an autosomal dominant fashion.[18] It has been suggested that the pharaohAkhenaten and other members of his family may have had this disorder,[19] but more recent genetic tests suggest otherwise.[20] It is one of the causes of familial precocious puberty—a condition first described in 1937.[21]
This syndrome is due to aloss of function mutation within the CYP19A1 gene and is inherited in anautosomal recessive way. Accumulations of androgens during pregnancy may lead tovirilization of a female at birth (males are not affected). Females will have primaryamenorrhea. Individuals of both sexes will be tall, as lack of estrogen preventsepiphyseal closure.
^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^Vaz AD (2003). "Chapter 1: Cytochrome activation by cytochromes P450: a role for multiple oxidants in the oxidation of substrates". In Fisher M, Lee JK, Obach RE (eds.).Drug metabolizing enzymes: cytochrome P450 and other enzymes in drug discovery and development. Lausanne, Switzerland: FontisMedia SA.ISBN978-0-8247-4293-5.
^abcdDuffy 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".Journal of Experimental Zoology Part A.313 (7):421–31.Bibcode:2010JEZA..313..421D.doi:10.1002/jez.612.PMID20623799.
^Gilbert SF (2010).Developmental biology. Sunderland, Mass: Sinauer Associates.ISBN978-0-87893-384-6.
^Garcia-Segura LM, Wozniak A, Azcoitia I, Rodriguez JR, Hutchison RE, Hutchison JB (March 1999). "Aromatase expression by astrocytes after brain injury: implications for local estrogen formation in brain repair".Neuroscience.89 (2):567–78.doi:10.1016/s0306-4522(98)00340-6.PMID10077336.S2CID24689059.
^Saldanha CJ, Rohmann KN, Coomaralingam L, Wynne RD (August 2005). "Estrogen provision by reactive glia decreases apoptosis in the zebra finch (Taeniopygia guttata)".Journal of Neurobiology.64 (2):192–201.doi:10.1002/neu.20147.PMID15818556.
^Ziora K, Oświecimska J, Geisler G, Broll-Waśka K, Szalecki M, Dyduch A (2006). "[Familial precocious puberty -- a variant of norm or pathology?]".Endokrynologia, Diabetologia I Choroby Przemiany Materii Wieku Rozwojowego (in Polish).12 (1):53–8.PMID16704862.
^Satoh K, Sakamoto Y, Ogata A, Nagai F, Mikuriya H, Numazawa M, et al. (July 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.
Chen S (August 1998). "Aromatase and breast cancer".Frontiers in Bioscience.3 (4) A333: d922–33.doi:10.2741/A333.PMID9696881.
Strobel HW, Thompson CM, Antonovic L (June 2001). "Cytochromes P450 in brain: function and significance".Current Drug Metabolism.2 (2):199–214.doi:10.2174/1389200013338577.PMID11469726.
Bulun SE, Yang S, Fang Z, Gurates B, Tamura M, Zhou J, et al. (December 2001). "Role of aromatase in endometrial disease".The Journal of Steroid Biochemistry and Molecular Biology.79 (1–5):19–25.doi:10.1016/S0960-0760(01)00134-0.PMID11850203.S2CID7642211.
Balthazart J, Baillien M, Ball GF (December 2001). "Phosphorylation processes mediate rapid changes of brain aromatase activity".The Journal of Steroid Biochemistry and Molecular Biology.79 (1–5):261–77.doi:10.1016/S0960-0760(01)00143-1.PMID11850233.S2CID34269540.
Richards JA, Petrel TA, Brueggemeier RW (February 2002). "Signaling pathways regulating aromatase and cyclooxygenases in normal and malignant breast cells".The Journal of Steroid Biochemistry and Molecular Biology.80 (2):203–12.doi:10.1016/S0960-0760(01)00187-X.PMID11897504.S2CID12728545.
Balthazart J, Baillien M, Ball GF (May 2002). "Interactions between aromatase (estrogen synthase) and dopamine in the control of male sexual behavior in quail".Comparative Biochemistry and Physiology. Part B, Biochemistry & Molecular Biology.132 (1):37–55.doi:10.1016/S1096-4959(01)00531-0.PMID11997208.
Bulun SE, Takayama K, Suzuki T, Sasano H, Yilmaz B, Sebastian S (February 2004). "Organization of the human aromatase p450 (CYP19) gene".Seminars in Reproductive Medicine.22 (1):5–9.doi:10.1055/s-2004-823022.PMID15083376.S2CID260316748.
Bulun SE, Fang Z, Imir G, Gurates B, Tamura M, Yilmaz B, et al. (February 2004). "Aromatase and endometriosis".Seminars in Reproductive Medicine.22 (1):45–50.doi:10.1055/s-2004-823026.PMID15083380.S2CID260319473.
Chen S, Ye J, Kijima I, Kinoshita Y, Zhou D (May 2005). "Positive and negative transcriptional regulation of aromatase expression in human breast cancer tissue".The Journal of Steroid Biochemistry and Molecular Biology.95 (1–5):17–23.doi:10.1016/j.jsbmb.2005.04.002.PMID15955695.S2CID22138523.
Lambard S, Silandre D, Delalande C, Denis-Galeraud I, Bourguiba S, Carreau S (May 2005). "Aromatase in testis: expression and role in male reproduction".The Journal of Steroid Biochemistry and Molecular Biology.95 (1–5):63–9.doi:10.1016/j.jsbmb.2005.04.020.PMID16019206.S2CID40087589.
Bulun SE, Imir G, Utsunomiya H, Thung S, Gurates B, Tamura M, et al. (May 2005). "Aromatase in endometriosis and uterine leiomyomata".The Journal of Steroid Biochemistry and Molecular Biology.95 (1–5):57–62.doi:10.1016/j.jsbmb.2005.04.012.PMID16024248.S2CID37228186.
Ellem SJ, Risbridger GP (March 2006). "Aromatase and prostate cancer".Minerva Endocrinologica.31 (1):1–12.PMID16498360.
Brueggemeier RW, Díaz-Cruz ES (March 2006). "Relationship between aromatase and cyclooxygenases in breast cancer: potential for new therapeutic approaches".Minerva Endocrinologica.31 (1):13–26.PMID16498361.
Jongen VH, Hollema H, Van Der Zee AG, Heineman MJ (March 2006). "Aromatase in the context of breast and endometrial cancer. A review".Minerva Endocrinologica.31 (1):47–60.PMID16498363.
Hiltunen M, Iivonen S, Soininen H (March 2006). "Aromatase enzyme and Alzheimer's disease".Minerva Endocrinologica.31 (1):61–73.PMID16498364.
