Aromatase Inhibitors

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Aromatase is a cytochrome P450 enzyme complex that catalyzes the conversion of androstenedione to estrone and testosterone to estradiol (Figs. 25.5 and 25.16).67-69 The complex is made up of reduced nicotinamide adenine dinu-cleotide phosphate (NADPH)-cytochrome P450 reductase, and cytochrome P450 hemoprotein. In the first two steps, the C19 methyl is hydroxylated to CH2OH, and then to an alde hyde hydrate form that dehydrates to provide the C19 aldehyde. In the final aromatization step, the C19 carbon is ox-idatively cleaved to formate. A hydride shift, proton transfer, and free radical pathways have been proposed, with ciselimination of the 1j8 and hydrogens.70 In premenopausal women, aromatase is primarily found in ovaries, but in post-menopausal women, aromatase is largely in muscle and adipose tissue.

As discussed previously with SERMs, some types of breast cancer are estrogen dependent. Because the aromatase reaction is unique in steroid biosynthetic pathways, it would be anticipated that aromatase inhibitors would be very specific in their estrogen biosynthesis blockade. This has proved to be true, and aromatase inhibitors offer a useful approach to decreasing estrogen levels in the treatment of estrogen-dependent breast cancer. Initially, aromatase inhibitors were used as second-line therapy in postmenopausal women who failed on tamoxifen therapy. Recent studies have indicated, however, that the newer aromatase inhibitors can be used as first-line therapy and possibly for cancer prevention in patients at high risk.71

Aromatase inhibitors include both steroidal and nonsteroidal compounds. Examples of aromatase inhibitors are shown in Fig. 25.17. The first-generation aromatase inhibitors

Figure 25.17 • Aromatase inhibitors.

Figure 25.17 • Aromatase inhibitors.

were aminoglutethimide, a nonsteroidal compound, and the steroid-based testolactone, two compounds that were developed before it was recognized that their effectiveness in breast cancer treatment was caused by aromatase inhibition.72 Aminoglutethimide also inhibits other P450s involved in steroid hormone biosynthesis, which limits its use in breast cancer treatment. The newer drugs are more potent and more specific inhibitors of aromatase than the earlier compounds.

Exemestane is a newer steroidal aromatase inhibitor. It is an enzyme activated irreversible ("suicide") inhibitor of aromatase. It is orally available and highly selective for aromatase. Its structure reflects only minor structural modifications to the natural substrate, androstenedione.

The nonsteroidal aromatase inhibitors are competitive inhibitors that bind to the enzyme active site by coordinating the iron atom present in the heme group of the P450 protein. Aside from aminoglutethimide, the first selective aromatase inhibitor to be marketed in the United States was anastrozole (Arimidex). Anastrozole incorporates a triazole ring into its structure that can coordinate to the heme iron. Letrozole is another triazole-containing inhibitor that is also effective in the treatment of breast cancer.

Currently available inhibitors suppress plasma estrogen levels (estradiol, estrone, and estrone sulfate) by 80% to 95%. Earlier aromatase inhibitors, such as aminoglutethimide and testolactone, suppressed plasma estrogens to a lesser extent. The side effects often seen with aminoglutethimide because of additional inhibition of other biosynthetic enzymes are avoided with the newest agents. The selectivity of these drugs for aromatase is quite high.

As with the SERMs, these drugs are only effective when the breast cancer cells are "ER positive," meaning that they respond and proliferate in the presence of estrogen. Aromatase inhibitors can cause fetal harm in pregnant women and are therefore contraindicated.

Additional nonsteroidal inhibitors are based on the flavone structure. Chrysin is a flavonoid natural product that has aromatase inhibitory action in vitro similar to that of aminoglutethimide.73 It is isolated from Passiflora coerulea and other plants. While this compound is not used therapeu-tically as an aromatase inhibitor, it has found questionable use as a nutritional supplement either alone or in combination with anabolic steroids to enhance muscle building and athletic performance. The theory for use is that an aromatase inhibitor allows the estrogenic side effects of androgenic compounds to be reduced. Although various nutritional supplement products containing chrysin are available, it is unclear whether or not significant aromatase inhibition is being achieved in vivo. The oral bioavailability of chrysin is very low, mainly as a result of efficient conversion to the corresponding glucuronide and sulfate conjugates, so the plasma concentration of free chrysin is minimal.74

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