Wyllie S, Liehr J G
Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston 77555-1031, USA.
Arch Biochem Biophys. 1997 Oct 15;346(2):180-6. doi: 10.1006/abbi.1997.0306.
Estrogens induce hydroxyl radical-mediated DNA and protein damage and lipid peroxidation. As part of a study of the mechanism of hydroxyl radical generation by estrogens, we investigated the in vitro mobilization of Fe2+ from ferritin by redox cycling of the stilbene or steroid estrogen metabolites diethylstilbestrol-4',4"-quinone (DESQ), equilenin-3,4-quinone (EQ), or estrone-3,4-quinone (3,4EQ). Aerobic cytochrome P450 reductase-mediated redox cycling of 35.50 microM DESQ, 0.35 microM EQ, or 3.55 microM 3,4EQ increased the reduction of succinoylated cytochrome c, a measure of superoxide radical formation, by 19-20% over control values (24.5+/-0.3 microM) in the absence of estrogen quinone substrate. Rates of Fe2+ release from horse spleen ferritin by cytochrome P450 reductase-mediated redox cycling of 35.50 microM DESQ, 0.35 microM EQ, or 3.55 microM 3,4EQ were 94.4+/-0.6, 117.2+/-9.4, or 137.7+/-19.9 pmol Fe2+/min, respectively, compared to 67.3 + 2.3 pmol Fe2+/min in the absence of estrogen substrates. Redox cycling of 35.5 microM DESQ, EQ, or 3,4EQ mediated by microsomes of hamster kidney, a target organ of estrogen-induced carcinogenesis, released 511+/-30.10, 516.91+/-22.90, or 410.27+/-28.49 pmol Fe2+/min, respectively. Corresponding values with microsomes of hamster liver, where tumors do not develop by estrogen treatment, were 272.27+/-43.10, 222.25+/-21.78, or 91.36+/-8.54 pmol Fe2-/min, respectively. Diethylstilbestrol, equilenin, and 4-hydroxyestrone do not induce detectable iron release from ferritin under these conditions. The cytochrome P450 reductase-mediated redox cycling of DESQ, EQ, or 3,4EQ in the presence of iron resulted in the hydroxylation of benzoic acid by hydroxyl radical attack. These data demonstrate that redox cycling of estrogen metabolites releases Fe2+ from ferritin, which in turn generates hydroxyl radicals by a Fenton reaction. This estrogen-induced hydroxyl radical damage may contribute to tumor initiation in hormone target tissues, including breast cancer.
雌激素可诱导羟基自由基介导的DNA和蛋白质损伤以及脂质过氧化。作为雌激素产生羟基自由基机制研究的一部分，我们研究了二苯乙烯或类固醇雌激素代谢产物己烯雌酚 - 4',4"-醌（DESQ）、马萘雌酮 - 3,4 - 醌（EQ）或雌酮 - 3,4 - 醌（3,4EQ）通过氧化还原循环从铁蛋白中体外动员Fe2+的情况。需氧细胞色素P450还原酶介导的35.50 microM DESQ、0.35 microM EQ或3.55 microM 3,4EQ的氧化还原循环使琥珀酰化细胞色素c的还原增加，这是超氧自由基形成的一种度量，与在没有雌激素醌底物时的对照值（24.5±0.3 microM）相比增加了19 - 20%。细胞色素P450还原酶介导的35.50 microM DESQ、0.35 microM EQ或3.55 microM 3,4EQ的氧化还原循环使马脾铁蛋白释放Fe2+的速率分别为94.4±0.6、117.2±9.4或137.7±19.9 pmol Fe2+/min，而在没有雌激素底物时为67.3 + 2.3 pmol Fe2+/min。雌激素诱导致癌作用的靶器官仓鼠肾微粒体介导的35.5 microM DESQ、EQ或3,4EQ的氧化还原循环分别释放511±30.10、516.91±22.90或410.27±28.49 pmol Fe2+/min。用雌激素处理不会发生肿瘤的仓鼠肝微粒体的相应值分别为272.27±43.10、222.25±21.78或91.36±8.54 pmol Fe2 - /min。在这些条件下，己烯雌酚、马萘雌酮和4 - 羟基雌酮不会诱导铁蛋白释放可检测到的铁。在铁存在的情况下，细胞色素P450还原酶介导的DESQ、EQ或3,4EQ的氧化还原循环导致苯甲酸被羟基自由基攻击而发生羟基化。这些数据表明，雌激素代谢产物的氧化还原循环从铁蛋白中释放Fe2+，进而通过芬顿反应产生羟基自由基。这种雌激素诱导的羟基自由基损伤可能有助于激素靶组织（包括乳腺癌）中的肿瘤起始。
