loped; the third generation is currently being used. The inhibitors can be further classified as type I or type II depending on whether the inhibition is irreversible or reversible. An example of third generation type I drug is the steroidal analog exemestane (Aromasin); examples of type II third generation drugs include the non-steroidal agents anastrozole (Arimidex) and letrozole (Femara). In many species, including most mammals, one aromatase enzyme encoded by Cyp19a1 gene is present in the family. Aromatase converts the C19 androstenedione and testosterone to C18 estrone and estradiol, respectively, in a three step reaction process, each requiring one mole of oxygen and of NADPH and electrons supplied by the P450 oxidoreductase Por. The first two hydroxylation steps occur at the C19 methyl group of androgen and are rather typical P450 hydroxylation reactions; the third step which results in the cleavage of C10-C19 bond and aromatization of the steroid A ring is unique to aromatase. The major structural difference between androgen and estrogen is the A ring which is planar aromatic in estrogen while the androgen has a non-aromatic 6-carbon ring. Studies have shown that both Por and Cyp19a1 are attached to the ER membrane. The structure of the aromatase bound to androstenedione shows the substrate fitting snugly in the active site cavity, at the heme distal site. The androgen/substrate specificity is another unique feature of the aromatase. Steroidal drugs such as exemestane which is an analog of androstenedione are recognized as substrates. Exemestane is believed to be converted into a reactive intermediate that covalently and irreversibly binds to the enzyme's substrate site permanently inactivating it. Such inhibitors are also referred to as 'suicide' inhibitors. Non-steroidal agents bind non-covalently to the aromatase heme moiety thus occupying the substrate-binding site and this action is reversible as endogenous substrate can competitively displace them. The non-steroidal letrozole appears to be a somewhat more potent aromatase inhibitor than other drugs. In advanced disease settings, aromatase inhibitors appear to be superior to antagonists such as tamoxifen. However, like in the case of tamoxifen, initial positive responses can eventually turn to resistance. In addition, adverse side effects such as increase in osteoporosis and arthralgia have been reported.
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