Reactome | CYP19A1 binds Aromatase inhibitors

CYP19A1 binds Aromatase inhibitors

Stable Identifier

R-HSA-9707353

Type

Reaction [binding]

Species

Homo sapiens

Compartment

cytosol, endoplasmic reticulum membrane

ReviewStatus

5/5

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CYP19A1 (aromatase) is the enzyme that catalyses a key aromatization step in the synthesis of estrogens from androgens. Aromatase inhibitors work by inhibiting the action of the enzyme aromatase (Brodie et al. 1981). Many breast cancers are hormone receptor-positive, meaning their growth is stimulated and/or maintained by the presence of hormones such as estrogen or progesterone. In postmenopausal women, estrogen is primarily derived from the aromatization of adrenally-produced androgens into estrogens by CYP19A1. Aromatase inhibitors are a class of drugs used in the treatment of breast cancer in postmenopausal women by competitively inhibiting CYP19A1. As breast tissue is stimulated by estrogens, decreasing their production is a way of suppressing growth of hormone receptor-positive breast tumours (Chumsri et al. 2011). Aromatase inhibitors can be first-generation (e.g. aminoglutethimide) (Greco et al. 2005), second-generation (e.g. fadrozole) (Browne et al. 1991), and third-generation (e.g. anastrozole, letrozole, and exemestane) (Bhatnagar et al. 1990, Cohen et al. 2002, Buzdar et al. 2002) agents. They can also be divided into type I and type II inhibitors. Type I inhibitors have a steroidal structure similar to androgens and inactivate CYP19A1 irreversibly by blocking the substrate-binding site, and are therefore known as aromatase inactivators. Type II inhibitors are nonsteroidal and their action is reversible.

Literature References

PubMed ID	Title	Journal	Year
1825337	Fadrozole hydrochloride: a potent, selective, nonsteroidal inhibitor of aromatase for the treatment of estrogen-dependent disease Gude, C, Steele, RE, Bhatnager, A, Rodriguez, H, Browne, LJ	J Med Chem	1991
16332571	HPMA copolymer-aminoglutethimide conjugates inhibit aromatase in MCF-7 cell lines Penning, NA, Greco, F, Nicholson, RI, Vicent, MJ, Duncan, R	J Drug Target	2005
12404296	An overview of the pharmacology and pharmacokinetics of the newer generation aromatase inhibitors anastrozole, letrozole, and exemestane Nabholtz, JM, Robertson, JF, Buzdar, AU, Eiermann, W	Cancer	2002
2149502	Highly selective inhibition of estrogen biosynthesis by CGS 20267, a new non-steroidal aromatase inhibitor Schieweck, K, Bowman, R, Häusler, A, Bhatnagar, AS, Lang, M	J Steroid Biochem Mol Biol	1990
7336466	Inactivation of aromatase in vitro by 4-hydroxy-4-androstene-3,17-dione and 4-acetoxy-4-androstene-3,17-dione and sustained effects in vivo Robinson, CH, Brodie, AM, Marcotte, PA, Garrett, WM, Hendrickson, JR, Tsai-Morris, CH	Steroids	1981
11895893	Approval summary: letrozole in the treatment of postmenopausal women with advanced breast cancer Cohen, MH, Li, N, Pazdur, R, Chen, G, Johnson, JR	Clin Cancer Res	2002