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<p>For medical applications of photosensitization, it is crucial to identify the reactive species generated. Previous studies have shown that during photosensitization, the nitrone spin trap 5,5-dimethyl-1-pyrroline-<i>N</i>-oxide (DMPO) converts singlet oxygen (<sup>1</sup>O<sub>2</sub>) to hydroxyl radical (<sup>•</sup>OH), producing the electron spin resonance (ESR) signal of DMPO-OH adduct. This signal is strongly enhanced by biological reductants such as reduced <i>β</i>-nicotinamide adenine dinucleotide phosphate, reduced glutathione, or phenolic compounds. In this study, we investigated the mechanism of DMPO-OH formation and the role of reductants during uroporphyrin-mediated photosensitization in an aqueous solution. Kinetic analyses revealed that the initial rate of DMPO-OH formation remained constant despite varying reductant concentrations. <sup>1</sup>O<sub>2</sub> was found to react with DMPO independently of reductants, as indicated by oxygen consumption. Similarly, the formation of <sup>•</sup>OH, monitored via 2,3-dihydroxybenzoic acid derived from salicylic acid, increased in the presence of DMPO regardless of the presence of reductants. Both DMPO-OH formation and oxygen consumption decreased under alkaline conditions. When the spin traps, 5-(diethoxyphosphoryl)-5-methyl-1-pyrroline-<i>N</i>-oxide (DEPMPO), 5-ethoxycarbonyl-5-methyl-1-pyrroline-<i>N</i>-oxide (EMPO), 5-<i>tert</i>-butoxycarbonyl-5-methyl-1-pyrroline-<i>N</i>-oxide (BMPO), and 3,3,5,5-tetramethyl-1-pyrroline-<i>N</i>-oxide (M<sub>4</sub>PO) were used, <sup>•</sup>OH adduct formation followed the order M<sub>4</sub>PO &gt; DMPO &gt; &gt; DEPMPO, EMPO, BMPO; the opposite trend to that observed for pseudo-<sup>•</sup>OH adducts formation via nucleophilic substitution with water. These findings suggest that <sup>1</sup>O<sub>2</sub> electrophilically reacts with nitrone spin traps, and that <sup>•</sup>OH is likely released from the resulting hydroperoxide intermediate. Reductants may not contribute to the <sup>•</sup>OH generation but instead stabilize the DMPO-OH formed. This <sup>•</sup>OH adduct formation can be suppressed by using spin traps with electron-withdrawing substituents.</p>

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Spin trap-mediated conversion of singlet oxygen to hydroxyl radical in photosensitization: mechanistic insights and the role of biological reductants

  • 期刊论文

  • 发表日期：

    2026年7月9日

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  • Chiho Nishizawa,
  • Shoko Okazaki,
  • Keizo Takeshita,
  • Toshihiko Ozawa

摘要

For medical applications of photosensitization, it is crucial to identify the reactive species generated. Previous studies have shown that during photosensitization, the nitrone spin trap 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) converts singlet oxygen (1O2) to hydroxyl radical (•OH), producing the electron spin resonance (ESR) signal of DMPO-OH adduct. This signal is strongly enhanced by biological reductants such as reduced β-nicotinamide adenine dinucleotide phosphate, reduced glutathione, or phenolic compounds. In this study, we investigated the mechanism of DMPO-OH formation and the role of reductants during uroporphyrin-mediated photosensitization in an aqueous solution. Kinetic analyses revealed that the initial rate of DMPO-OH formation remained constant despite varying reductant concentrations. 1O2 was found to react with DMPO independently of reductants, as indicated by oxygen consumption. Similarly, the formation of •OH, monitored via 2,3-dihydroxybenzoic acid derived from salicylic acid, increased in the presence of DMPO regardless of the presence of reductants. Both DMPO-OH formation and oxygen consumption decreased under alkaline conditions. When the spin traps, 5-(diethoxyphosphoryl)-5-methyl-1-pyrroline-N-oxide (DEPMPO), 5-ethoxycarbonyl-5-methyl-1-pyrroline-N-oxide (EMPO), 5-tert-butoxycarbonyl-5-methyl-1-pyrroline-N-oxide (BMPO), and 3,3,5,5-tetramethyl-1-pyrroline-N-oxide (M4PO) were used, •OH adduct formation followed the order M4PO > DMPO > > DEPMPO, EMPO, BMPO; the opposite trend to that observed for pseudo-•OH adducts formation via nucleophilic substitution with water. These findings suggest that 1O2 electrophilically reacts with nitrone spin traps, and that •OH is likely released from the resulting hydroperoxide intermediate. Reductants may not contribute to the •OH generation but instead stabilize the DMPO-OH formed. This •OH adduct formation can be suppressed by using spin traps with electron-withdrawing substituents.