title: Mechanistic investigations on the antioxidant action of a neuroprotective estrogen derivative.
abstract: Antioxidant action is an important component of the complex neuroprotective effect 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 17beta-butoxy-1,3,5(10)-estratrien-3-ol, a synthetic derivative of 17beta-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 10beta-hydroxy-17beta-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 estrogen-derived compounds.
authors: Department of Pharmacology and Neuroscience, UNT Health Science Center, Fort Worth, TX 76107, USA.
authors: Katalin
authors: K
authors: Prokai-Tatrai
authors: Pal
authors: P
authors: Perjesi
authors: Nilka M
authors: NM
authors: Rivera-Portalatin
authors: James W
authors: JW
authors: Simpkins
authors: Laszlo
authors: L
authors: Prokai
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis / Q000494:pharmacology*; D002478:Cells, Cultured; D004958:Estradiol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D004967:Estrogens / Q000138:chemical synthesis / Q000494:pharmacology*; D016166:Free Radical Scavengers / Q000138:chemical synthesis / Q000494:pharmacology; D017665:Hydroxyl Radical / Q000737:chemistry; D015227:Lipid Peroxidation; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress; D011960:Receptors, Estrogen / Q000378:metabolism
chemical_list: C528945:10-hydroxy-17-butoxy-1,3,5(10)-estratrien-3-one; C528944:17-butoxy-1,3,5(10)-estratrien-3-ol; D000975:Antioxidants; D004967:Estrogens; D016166:Free Radical Scavengers; D018696:Neuroprotective Agents; D011960:Receptors, Estrogen; D017665:Hydroxyl Radical; D004958:Estradiol