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  • ddhGTP br Aromatase inhibitors The aromatase enzyme P arom b

    2023-01-31


    Aromatase inhibitors The aromatase enzyme, P450arom, belongs to the super-family of P450 proteins which includes more than 480 members divided in 74 different families. P450arom is a unique member of family 19 [39], and is located in the endoplasmic reticulum of mammalian ddhGTP that express the CYP19 gene, such as adipose tissue, brain, adrenal glands, gonads, liver and placenta [40], [41], [42]. P450arom contains a heme group in its structure and is functionally associated with another member of P450 cytochrome family, NADPH reductase, which acts as a donor of reductive equivalents [39]. It is responsible for catalyzing the final, rate-limiting step in the production of estrogens (estrone and estradiol) from C19 substrate (androstenedione and testosterone). Aromatase inhibitors have been classified as Type I or Type II based on their chemical structure and mechanism of action. Steroidal aromatase inhibitors (Type I) are compounds derived from androstenedione. These compounds bind irreversibly to the active site of P450arom inducing a covalent change on the structure of the enzyme which results in lasting and selective inhibition. Because of their irreversible effects, these compounds are also called “suicide inactivators”. Formestane and exemestane are examples of Type I inhibitors [43]. Non-steroidal aromatase inhibitors (Type II) are compounds that have a nitrogen containing heterocyclic moiety, the triazole group, as a common characteristic of their chemical structure. These inhibitors bind to the heme group in the P450arom, occupying part of the active binding site of the enzyme and interfering with enzyme activity in a reversible way. Examples of these Type II estrogen synthetase-specific inhibitors are letrozole, anastrozole, and fradozole [43]. Since steroidal aromatase inhibitors mimic the structure of androstenedione, they have been associated with undesired mild androgenic effects. Furthermore, the irreversible nature of the inhibitor-enzyme interaction implies that recovery of estrogen production will be delayed after treatment is stopped because it is dependent on de novo synthesis of P450arom protein [44]. Exemestane, letrozole and anastrozole are the most recently developed, 3rd generation aromatase inhibitors. The main difference between 2nd (fadrozole and formestane) and 3rd generation aromatase inhibitors is improved specificity in the latter, which has reduced secondary effects of non-specific enzymatic inhibition [45]. Letrozole (MW 285.3 g/mol, Fig. 1) has been the focus of most recent studies on the use of aromatase inhibitors in human and veterinary medicine as it is a potent non-steroidal aromatase inhibitor that is highly specific for P450arom, and reversibly inhibits the enzyme without altering progesterone or corticosteroid synthesis [46], [47], [48].
    Clinical use of aromatase inhibitors
    Effects on ovarian function
    Development of a letrozole-releasing vaginal device Growing interest in aromatase inhibitor-based protocols to control ovarian function in mammals has created a need for the development of effective routes and vehicles of administration to ensure the desired biological effect. Regarding prolonged treatment, the intravaginal route has advantages over other routes in that it is well-tolerated, easily applied, has a high retention rate, enables controlled withdrawal, and in animals, it reduces the number of handlings required [84]. An initial study of intravaginal drug delivery cattle was designed to test the hypotheses that extended letrozole treatment, initiated prior to selection of the preovulatory dominant follicle, will induce the growth of more than one follicle to a pre-ovulatory size, and will delay ovulation [85]. Co-dominance was not observed, but treatment delayed ovulation by 24 h and resulted in the formation of a CL that secreted higher levels of progesterone. The half-life of letrozole observed following administration via an intravaginal device (33 h) corresponded with that reported previously after single intravenous administration in beef heifers [78], but based on the plasma letrozole concentration profile, the formulation of the intravaginal devices released letrozole for only 24 h post-insertion. Hence, the relatively rapid decline in circulating letrozole was associated with only a 24-h delay in the pre-ovulatory estradiol rise compared to untreated controls.