Mechanistic investigations on the antioxidant action of a neuroprotective estrogen derivative

Abstract

Antioxidant action is an important component of the complex neuroprotective action of estrogens. Combining theoretical prediction and subsequent experimental confirmation by chemical and in vitro paradigms, this study focused on the mechanistic aspects of hydroxyl-radical scavenging by 17β-butoxy-1,3,5(10)-estratrien-3-ol, a synthetic derivative of 17β-estradiol with increased potency to inhibit lipid peroxidation and reduced affinity to estrogen-receptors compared to the endogenous hormone. In the process that acts as a "chemical shield," the phenolic A-ring turns into 10β-hydroxy-17β-butoxy-1,3,5(10)-estratrien-3-one, a non-aromatic para-quinol, upon capturing hydroxyl-radicals, which results in the complete loss of estrogen-receptor affinity and antioxidant activity. However, the parent compound is apparently recovered in brain tissue from this para-quinol via enzyme-catalyzed NAD(P)H-dependent reductive aromatization without causing oxidative stress. Taken together, our report argues for a previously unrecognized antioxidant cycle for synthetic estrogen-derived compounds.

Protective effects of oestradiol against cadmium-induced changes in blood parameters and oxidative damage in rats

“…Previous studies (11,13) suggest that this is mediated by the phenol hydroxyl group of E2, which donates hydrogen atoms to a lipidderived radical. The resulting oestrogen phenoxyl radical is stabilised by delocalisation of unpaired electrons in the aromatic ring (13,14). Oestrogens thus prevent LPO by sacrificing themselves to oxidation, turning into quinol, which can be formed directly from E2 and ·OH without the participation of metabolic enzymes, and by converting back to E2 using NADPH as the reducing agent without the production of ROS (13,38).…”

“…A number of studies have already established its protective role in the cardiovascular and nervous system (14,15), but little is known about its effects against Cd toxicity in blood in vivo.…”

Estrogen and Brain Protection

“…The phenoxyl radical ring is converted to para-quinol ring by scavenging further free radicals like -OH. This para-quinol ring structure finally becomes the original A ring of 17 -estradiol through NADPH (Prokai et al, 2003;Prokai-Tatrai et al, 2008). The important point of this cyclic reaction is that 17 -estradiol is rejuvenated after it absorbs harmful free radicals (Figure 2).…”

“…The quinol is rapidly converted to the parent estrogen via a NAD(P)Hdependent reductive aromatization to perpetuate the antioxidant action. During this process, •OH is detoxified to H 2 O (Prokai et al, 2003;Prokai-Tatrai et al, 2008).…”

Approaches for Searching of Modified Steroid Estrogen Analogues with Improved Biological Properties

“…Oxygen atom does obviously possess a big influence on electron density distribution in A ring, which can have an impact on antioxidant properties of such compounds. Difference in antioxidant action mechanisms between such compounds and those discussed earlier can be assumed (Prokai-Tatrai et al, 2008 Table 2. Results of investigation of action of steroid 102 on lipid peroxidation in brain of rats Steroid was given per os in olive oil in dose 5 mg per 100 g of weight of rats, for the day before the slaughter.…”