Steroid sulfatase inhibitors promising new therapy for breast cancer

As a mitochondrial P450 system, P450c11 is dependent on two electron transfer proteins, adrenodoxin reductase and adrenodoxin that transfer 2 electrons from NADPH to the P450 for each monooxygenase reaction catalyzed by the enzyme. In most respects this process of electron transfer appears similar to that of P450scc system that catalyzes cholesterol side chain cleavage. [9] Similar to P450scc the process of electrons transfer is leaky leading to superoxide production. The rate of electron leakage during metabolism depends on the functional groups of the steroid substrate. [10]

Restriction enzymes, such as Eco RI, are used in a wide variety of molecular genetics techniques including cloning , DNA screening and deleting sections of DNA in vitro . Restriction enzymes, like Eco RI, that generate sticky ends of DNA are often used to cut DNA prior to ligation , as the sticky ends make the ligation reaction more efficient. Eco RI can exhibit non-site-specific cutting, known as star activity , depending on the conditions present in the reaction. Conditions that can induce star activity when using Eco RI include low salt concentration, high glycerol concentration, excessive amounts of enzyme present in the reaction, high pH and contamination with certain organic solvents. [5]

5 alpha-dihydrotestosterone is known to play a crucial part in the regulation of hair growth and in the development of androgenetic alopecia. 5 alpha-dihydrotestosterone is formed locally within the hair follicle from the systemic precursor testosterone by cutaneous steroid 5 alpha-reductase. Moreover, adrenal steroids such as dehydroepiandrosterone are converted to 5 alpha-dihydrotestosterone by isolated hair follicles, which may provide an additional source of intrafollicular 5 alpha-dihydrotestosterone levels. Elevated urinary dehydroepiandrosterone and serum dehydroepiandrosterone sulfate have been reported to be present in balding young men. These reports suggest that dehydroepiandrosterone sulfate may act as an important endocrine factor in the development of androgenetic alopecia. Hence the question arises whether the dehydroepiandrosterone sulfate can be metabolized within the hair follicles to yield dehydroepiandrosterone by the microsomal enzyme steroid sulfatase, and where steroid sulfatase might be localized. We therefore performed immunostaining for steroid sulfatase on human scalp biopsies as well as analysis of steroid sulfatase enzyme activity in defined compartments of human beard and occipital hair follicles ex vivo. Using both methods steroid sulfatase was primarily detected in the dermal papilla. Steroid sulfatase activity was inhibited by estrone-3-O-sulfamate, a specific inhibitor of steroid sulfatase, in a concentration-dependent way. Furthermore, we show that dermal papillae are able to utilize dehydroepiandrosterone sulfate to produce 5 alpha-dihydrotestosterone, which lends further support to the hypothesis that dehydroepiandrosterone sulfate contributes to androgenetic alopecia and that steroid sulfatase inhibitors could be novel drugs to treat androgen-dependent disorders of the hair follicle such as androgenetic alopecia or hirsutism.

Steroid sulfatase inhibitors promising new therapy for breast cancer

steroid sulfatase inhibitors promising new therapy for breast cancer

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