Lapenna Domenico, Ciofani Giuliano, Festi Davide, Neri Matteo, Pierdomenico Sante D, Giamberardino Maria Adele, Cuccurullo Franco
Dipartimento di Medicina e Scienze dell'Invecchiamento, Facolta' di Medicina e Chirurgia, Universita' G. d'Annunzio, 66100 Scalo, Chieti, Italy.
Biochem Pharmacol. 2002 Dec 1;64(11):1661-7. doi: 10.1016/s0006-2952(02)01391-6.
We have investigated potential antioxidant properties of the clinically relevant bile acid UDCA, which reaches therapeutic concentrations up to 0.09 and 29 mM, respectively, in human plasma and bile. UDCA was an excellent scavenger of OHz.rad; generated by FeCl(3)-EDTA, H(2)O(2) and ascorbate in the deoxyribose oxidation test, showing IC(min) and IC(50) values of 0.02 and 0.2 mM, respectively, and a second-order rate constant for reaction with OHz.rad; of 2+/-0.1 x 10(10)M(-1)s(-1). Notably, the drug could enhance at 1.5 mM concentration the antioxidant capacity of human bile against OHz.rad;-induced deoxyribose oxidation. UDCA also showed antioxidant effects in the deoxyribose test performed with nonchelated iron ions, such as Fe(2+) plus H(2)O(2) (IC(min): 7 mM, IC(50): 20 mM) or Fe(3+) plus H(2)O(2) and ascorbate (IC(min): 0.3 mM, IC(50): 5 mM), and inhibited ferrozine-Fe(2+) and desferrioxamine-Fe(3+) complexes formation with IC(50) values of, respectively, 12 and 0.3 mM, indicating that the drug interacts more with iron(III) than with iron(II). Moreover, UDCA significantly inhibited phospholipid liposome peroxidation induced by the OHz.rad;-generating system FeCl(3)-EDTA, H(2)O(2) and ascorbate (IC(min): 0.75 mM, IC(50): 3 mM), and by peroxyl radicals generated in the aqueous phase by AAPH (IC(min): 8 mM, IC(50): 14 mM). UDCA, even at 25 mM concentration, was ineffective on the lipoperoxidation mediated by Fe(2+) alone, but at the same concentration counteracted significantly that by Fe(3+) plus ascorbate, further pointing to its preferential antioxidant interaction with iron(III). In conclusion, UDCA has direct antioxidant properties, which are especially relevant against Fe(3+)- and OHz.rad;-dependent biomolecular oxidative damage; such properties are evident at therapeutically relevant drug concentrations, suggesting that UDCA could act as an antioxidant in vivo.
我们研究了临床相关胆汁酸熊去氧胆酸（UDCA）的潜在抗氧化特性，在人体血浆和胆汁中，其治疗浓度分别可达0.09 mM和29 mM。在脱氧核糖氧化试验中，UDCA是由FeCl₃-EDTA、H₂O₂和抗坏血酸产生的·OH的优秀清除剂，其IC(min)和IC(50)值分别为0.02 mM和0.2 mM，与·OH反应的二级速率常数为(2±0.1)×10¹⁰ M⁻¹ s⁻¹。值得注意的是，该药物在1.5 mM浓度下可增强人胆汁对·OH诱导的脱氧核糖氧化的抗氧化能力。UDCA在使用非螯合铁离子（如Fe²⁺加H₂O₂或Fe³⁺加H₂O₂和抗坏血酸）进行的脱氧核糖试验中也显示出抗氧化作用（IC(min)：7 mM，IC(50)：20 mM；IC(min)：0.3 mM，IC(50)：5 mM），并抑制了亚铁嗪-Fe²⁺和去铁胺-Fe³⁺复合物的形成，IC(50)值分别为12 mM和0.3 mM，表明该药物与铁(III)的相互作用比与铁(II)的更强。此外，UDCA显著抑制了由·OH产生系统FeCl₃-EDTA、H₂O₂和抗坏血酸以及由偶氮二异丁腈（AAPH）在水相中产生的过氧自由基诱导的磷脂脂质体过氧化（IC(min)：0.75 mM，IC(50)：3 mM；IC(min)：8 mM，IC(50)：14 mM）。即使在25 mM浓度下，UDCA对单独由Fe²⁺介导的脂质过氧化也无效，但在相同浓度下可显著抵消由Fe³⁺加抗坏血酸介导的脂质过氧化，进一步表明其与铁(III)的优先抗氧化相互作用。总之，UDCA具有直接的抗氧化特性，尤其与对抗Fe(III)和·OH依赖性生物分子氧化损伤相关；这些特性在治疗相关药物浓度下很明显，表明UDCA在体内可能起到抗氧化剂的作用。
