Tissue-Specific Regulation of Aromatase Cytochrome P450 (CYP19) Expression
The conversion of androgens to estrogens is catalyzed by an enzyme complex known as aromatase, whose activity results in aromatization of the A ring of androgens, to form the phenolic A ring characteristic of estrogens with concomitant loss of the C19 angular methyl group. This enzyme complex is localized to the endoplasmic reticulum of cells in which it is expressed and consists of two components. The first is a form of cytochrome P450 known as aromatase cytochrome P450 (P450arom) (Mendelson et al. 1985; Chen et al. 1986; Kellis and Vickery 1987), the product of the CYP19 gene (Nebert et al. 1991). This heme protein is responsible for binding the C19 steroid substrate and catalyzing the concerted series of reactions leading to formation of the phenolic A ring. The second component is a flavoprotein, NADPH-cytochrome P450 reductase, which is a ubiquitous protein in the endoplasmic reticulum of most cell types and is responsible for transferring reducing equivalents from NADPH to any microsomal cytochrome P450 species with which it comes into contact. The aromatase reaction utilizes 3mol oxygen and 3mol NADPH for every mole of C19 steroid metabolized (Thompson and Siiteri 1974) (Fig. 1). There is general agreement that the first two oxygen molecules are utilized in the oxidation of the C19 angular methyl group. A growing consensus of opinion considers that the third oxygen attack is also on the C19 methyl group resulting in its loss as formic acid.
KeywordsObesity Chrome Testosterone Glucocorticoid NADPH
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- de Pragter-Holthuizen P, Jansen M, van der Kämmen RA, van Schaik FMA, Sussenbach JS (1988) Differential expression of the human insulin-like growth factor II gene. Characterization of the IGF-II mRNAs and an mRNA encoding a putative IGF-II-associated protein. Biochim Biophys Acta 950: 282–295Google Scholar
- Di Mattia GE, Gellerson B, Duckworth ML, Friesen GH (1990) Human prolactin gene expression: the use of an alternative noncoding exon in decidua and the IM-9-P3 lymphoblast cell line. J Biol Chem 265: 16412–16421Google Scholar
- Edman CD, MacDonald PC, Combes B (1975) Extraglandular production of estrogens in subjects with liver disease. Gastroenterology 69:819 Fritz IB, Griswold MD, Louis BF, Dorrignton JH (1976) Similarity of responses of cultured Sertoli cells to cholera toxin and FSH. Mol Cell Endocrinol 5: 289Google Scholar
- Hickey GJ, Krasnow JS, Beattie WG, Richards JS (1990) Aromatase cytochrome P450 in rat ovarian granulosa cells before and after luteinization; adenosine 3′,5′-monophosphate — dependent and independent regulation, cloning and sequencing of rat aromatase cDNA and 5′-genomic DNA. Mol Endocrinol 4: 3–12PubMedCrossRefGoogle Scholar
- Matsumine H, Herbert MA, Ignatius Ou SH, Wilson JD, McPhaul MJ (1991) Aromatase mRNA in the extragonadal tissues of chickens with the henny- feathering trait is derived from a distinctive promoter structure that contains a segment of a retrovival long terminal repeat. J Biol Chem 266: 19900–19907PubMedGoogle Scholar
- Mendelson CR, Wright EE, Evans CT, Porter JC, Simpson ER (1985) Preparation and characterization of polyclonal and monoclonal antibodies against human aromatase cytochrome P-450 and their use in its purification. Arch Biochem Bipphys 243:480–491 Mendelson CR, Corbin CJ, Smith ME, Smith J, Simpson ER (1986) Growth factors suppress and phorbol esters potentiate the action of dibutyryl cyclic AMP to stimulate aromatase activity of human adipose stromal cells. Endocrinology 118: 968CrossRefGoogle Scholar
- Nebert DW, Nelson DR, Coon MJ, Estabrook RW, Feyersisen R, Fujii-Kuriyama Y, Gonzalez FJ, Guengerich FP, Gunsalus IC, Johnson EF, Loper JC, Sato R, Waterman MR, Waxman DJ (1991) The P450 superfamily: update on new sequences, gene mapping and recommended nomenclature. DNA Cell Biol 10: 1–14PubMedCrossRefGoogle Scholar