Mechanism and Inhibition of Cytochrome P-450 Aromatase

The role of estrogen blockade in the treatment of certain neoplastic disorders has been of wide interest for a number of years. It has long been known that specific tumors, particularly breast cancer in women, can grow more rapidly in proportion to the surrounding levels of estrogen.¹Recent advances in the areas of molecular and cellular biology have led to a more detailed understanding of estrogen action. The estrogen receptor gene has been cloned, sequenced, and expressed.²The estrogen receptor protein seems to be composed of two nonoverlapping functional domains: the first domain has a high affinity for estrogen and the second has a high affinity for DNA. Upon binding of estrogen to the first domain, a conformational change is apparently triggered in the second domain, allowing it to productively interact with a specific sequence of DNA nucleotides known as a transcriptional enhancer region. The result of this interaction is the greatly increased production of mRNA from select genes, one or more of which is probably essential for efficient tumor cell growth.²One can envision that there are many levels at which medical intervention could lead to the inhibition of estrogen action. For practical reasons, most of the research effort has been concentrated on two approaches. The first is the development of estrogen receptor antagonists. The most well known of these compounds is the stilbene derivative tamoxifen. In 1988, tamoxifen ranked second in sales in the U.S. among drugs used to treat cancer, and it accounted for 75% of the market for drugs used to treat breast cancer.³The second approach, which is the main topic of this review, is directed at lowering estrogen levels by inhibiting estrogen biosynthesis. Because estrogen synthetase (aromatase) catalyzes the final step in estrogen production in humans (the conversion of steroidal androgens 1 to steroidal estrogens 4; see Scheme I), it has been the principal target of inhibition.