Aim of this research line is to examine the local activity of enzymes converting estrogenic compounds with low potency into compounds with high estrogenic action. The regulation of these enzymes is frequently un-balanced in estrogen dependent diseases, leading to overexposure to estrogens. Understanding the regulation and the aberrations in these metabolic steps leads to novel target discovery for drugs.
High levels of estrogens and high exposure to these steroid hormones lead to gynaecological disorders and cancers. In several cases, however, the level of circulating estrogens in the blood is normal, but rather the local concentration of these compounds in the target tissues is altered. Steroid metabolising enzymes are responsible for the tissue concentration of estrogenic compounds and for the in situ estrogenic potency.
Numerous enzymes are involved in these metabolisms. The steroid sulphatase activates sulphated compounds (i.e. inactive) present in the circulation into active compounds whereas the sulpho-transferase catalyses the opposite reaction; the 17β-hydroxysteroid-dehydrogenases convert 17β-estradiol (highly active estrogen) to estrone (low activity) and vice-versa; aromatase converts androgens into estrogens.
We can analyse the activity of these enzymes in biopsies from patients or in in vitro models of the human endometrium. Specifically, we have developed a HPLC-based method to measure the conversions of steroid hormones. Tissue lysates are incubated under specific enzymatic conditions to force reactions towards one direction (for instance estrone - E1 - into 17β-estradiol- E2 – or vice versa). Purification of the estrogens and derivatisation with a fluorescence compound [2-(4-carboxy-phenyl)-5,6-dimethyl benzimidazole; CDB] allows the easy and non-radioactive detection and quantification of the substrate used and the product formed.
We aim to identify those metabolic steps that are de-regulated in the diseased tissues and we aim to develop novel drugs that, by inhibiting the activity of these steps, may re-establish the correct metabolic balance.
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