Mechanistic investigations on the antioxidant action of a neuroprotective estrogen derivative.
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.
Prokai-Tatrai
Katalin
K
Department of Pharmacology and Neuroscience, UNT Health Science Center, Fort Worth, TX 76107, USA.
Perjesi
Pal
P
Rivera-Portalatin
Nilka M
NM
Simpkins
James W
JW
Prokai
Laszlo
L
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
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