Mechanism Of Aromatase Inhibition

Aromatase, a cytochrome P450-dependent enzyme, converts adrenal androgens into estrogens and accounts for most of the estrogen produced in postmenopausal women. Inhibition of aromatase depletes available estrogen, thus preventing estrogen-specific stimulation of the growth of breast cancer cells. The first aromatase inhibitor (AI) that was developed, aminoglutethimide, has clinical activity against breast cancer, but its use is limited by side effects from concomitant adrenal suppression. Second-generation agents have increased specificity for aromatase with improved tolerability. The third-generation AIs, including the non-steroidal agents anastrozole and letrozole and the steroidal agent exemestane, provide potent and highly selective aromatase inhibition. The non-steroidal agents function through reversible inhibition of the aromatase enzyme, whereas the ster-oidal agent forms irreversible bonds. AIs are contraindicated in premenopausal women because the small decrease in systemic estrogen levels through inhibition of peripheral aromatization may paradoxically stimulate ovarian estrogen production and negate any anti-breast cancer effects.

Use of third-generation AIs lowers total body aromatization and plasma estradiol levels by more than 95% (4,5). Some variation in the action of the third-generation AIs has been noted. Data from small studies suggest that letrozole has superior potency than the other agents, with a greater overall decrease in estrogen after short-term exposure (6). Furthermore, differences in cytochrome P450 inhibition between the steroidal and non-steroidal AIs may lead to variation in the risk of drug interactions (7). In general, however, all three agents have been shown to be both potent and selective.

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