Aromatase in primate pregnancy: a review.

Aromatase enzyme is a cytochrome P450 protein that can catalyze the aromatization of C 19 androgens and thus their conversion into estrogens. It is tissue-specifically expressed in primate placenta, connective tissue, ovary, and brain through alternative splicing of tissue selective promoters. Human aromatase activity is critical for maintenance of early and mid pregnancy and in regulating parturition in late pregnancy. It is also important in the development of fetal gonadocytes and the sexual differentiation of brain, especially the hypothalamic-gonadal axis. Exposure to aromatase inhibitors in primates significantly impairs pregnancy outcome. Recent case reports have described syndromes associated with rare autosomal recessive mutations in aromatase genes.

Assessing pregnancy risks of azole antifungals using a high throughput aromatase inhibition assay.

UNLABELLED: Human aromatase (CYP19) converts C19 androgens to aromatic C18 estrogenic steroids. Its activity is critical for early and mid pregnancy maintenance and in regulating parturition in late pregnancy. Past studies have utilized placental microsome tritiated water release assay to assess drug-hormone interactions with estrogen synthesis. We compared data from human placental assays with BD Gentest's high throughput recombinant CYP19 enzyme assay using the fluorometric substrate dibenzylfluorescein. We tested a panel of azole antifungal agents that are commonly administered to women of childbearing potential, for their potential to inhibit aromatase. Potency varied by several orders of magnitude. Plasma and tissue levels of some azole drugs following oral or topical administration are at or above these IC50 values. These include the oral agents fluconazole and ketoconazole, and the topical agents econazole, bifonazole, clotrimazole, miconazole, and sulconazole. CONCLUSIONS: 1. Recombinant enzyme assay data are comparable to the human placental assay data in both SAR rank order and potency. 2. Plasma and tissue levels of some azole drugs following oral or topical administration are at or above these IC50 values. Therefore, some azole drugs may disrupt estrogen production in pregnancy, affecting pregnancy outcome. 3. Recombinant CYP19 assay using the fluorometric substrate dibenzylfluorescein, demonstrates rapid screening potential for chemicals that may affect pregnancy outcome as a result of CYP19 inhibition.