自身光敏藥物氨甲蝶呤對錳的光氧化還原機制之研究

Photoredox Mechanism of Manganese via Self-Photosensitized Compound Methotrexate

蘇怡瑄(Yi-Hsuan Su)

指導教授 ： 林郁真

國立臺灣大學/工學院/環境工程學研究所/碩士(2019年)

https://doi.org/10.6342/NTU201901808

摘要

許多藥物無法經由傳統污水處理程序有效去除，導致其普遍殘留於環境水體並經歷各種自然淨化途徑；其中，太陽光降解反應及自然界豐富存在的二氧化錳礦物所造成的氧化還原作用為藥物於水環境內的關鍵自然淨化機制。許多藥物吸收太陽光能量後將誘發一系列的光化學反應；而有些藥物具自身光敏能力(self-photosensitization)，其照光後生成的激發態物質將會與二氧化錳產生交互作用，進而影響藥物及二氧化錳於水環境內的降解轉化。因此本研究選用一具自身光敏能力的藥物－氨甲蝶呤(methotrexate)為目標污染物，研究其與二氧化錳於太陽光照射下的氧化還原機制。
存在methotrexate與二氧化錳的溶液於模擬太陽光照射下，在溶液內可以測得29.5 µM的錳離子生成([methotrexate]0 = 20 µM, [MnO2]0 = 200 µM, pH0 = 7 and t = 8 hrs)；且越高的methotrexate初始濃度(10–40 µM)將導致越多的錳離子生成(0–82.0 µM)。然而，其它不具自身光敏能力的藥物(7-aminocephalosporanic acid及acetaminophen)與二氧化錳溶液照射模擬太陽光12至14小時後仍無法測得錳離子。此結果顯示具自身光敏能力的藥物受陽光照射後會使二氧化錳加速還原成錳離子；本研究亦進一步藉由抑制劑及曝氣試驗以釐清細部反應機制並瞭解關鍵反應物質(例如三重激發態物質或活性氧物質)。首先，藉由添加異丙醇(抑制•OH)的結果發現，•OH不會影響methotrexate降解及錳離子生成速率；然而添加山梨酸(抑制三重激發態物質)將會對於methotrexate降解及錳離子生成有明顯抑制效果。此外，於溶液中分別曝氮氣及氧氣的實驗結果得知，水中溶氧將會搶奪三重激發態物質的能量並進而抑制錳離子的生成。故由上述結果闡明，methotrexate經由光照激發所產生的三重激發態物質是使二氧化錳加速還原成錳離子的主因。
本研究亦推測當溶氧存在時，methotrexate於光反應過程產生的三重激發態物質會與溶氧反應並生成超氧離子()，而會將二價錳離子(由二氧化錳經還原反應後所產生)氧化為三價錳；此具氧化能力的三價錳將進一步使得methotrexate降解。本機制是經由以下實驗所驗證：methotrexate於純光解作用下只降解60%，然而額外添加二價錳離子並同時照光則可使methotrexate降解率大幅提升至100% ([methotrexate]0 = 20 µM, [Mn2+]0 = 200 µM, pH0 = 3 and t = 4 hrs)；但若於溶液內再添加對苯醌以抑制後，methotrexate的降解趨勢又與其純光解反應類似。本篇研究結果顯示，具自身光敏能力的藥物會影響二氧化錳礦物於陽光照射下的光氧化還原機制；而除本研究中的目標藥物methotrexate外，水體中存在其它同樣具自身光敏能力的藥物及有機物，因此本成果將有助於全盤瞭解此類化合物於自然水體內的環境宿命。

關鍵字

自身光敏藥物 ； 二氧化錳 ； 模擬太陽光 ； 氨甲蝶呤 ； 三重激發態物質 ； 超氧離子

並列摘要

Traditional wastewater treatment processes cannot effectively remove pharmaceuticals, resulting in their ubiquitous occurrence in aqueous environments and further undergo various natural attenuation pathways. Both sunlight photolysis and redox reactions resulting from abundantly occurred manganese dioxide minerals are the two vital processes for pharmaceuticals degradation. While pharmaceuticals absorbing solar light, series of photochemical reactions can be induced; a few pharmaceuticals possess self-photosensitization ability－these chemicals are able to be photo-triggered as excited species, which can interact with MnO2, further affecting the pharmaceuticals degradation and MnO2 transformation in aqueous systems. This work selects methotrexate, a self-photosensitized pharmaceutical, as the target compound aiming to explore the redox reactions between methotrexate and MnO2 under sunlight irradiation.
Under simulated sunlight irradiation of the solution containing methotrexate and MnO2, 29.5 µM of manganese ions were formed after 8 hours reaction ([methotrexate]0 = 20 µM, [MnO2]0 = 200 µM and pH0 = 7); higher initial methotrexate concentrations (10–40 µM) lead to an increase in manganese ions formation (0–82.0 µM). On the contrary, for other pharmaceuticals which do not possess self-photosensitized reaction (7-aminocephalosporanic acid and acetaminophen), manganese ions were not detected within 12–14 hours irradiation. This indicated that under sunlight irradiation, the presence of self-photosensitized compounds accelerates the reduction of MnO2 into manganese ions. The detailed mechanism and key reactive species participated in the reaction were further elucidated by radicals scavenging and gas-sparging experiments. Isopropanol was used to scavenge hydroxyl radical (•OH) in the solution, and •OH did not affect the rates of methotrexate degradation and manganese ions formation; however, adding sorbic acid to quench triplet excited species significantly inhibited both the methotrexate degradation and manganese ions generation. Additionally, the results of N2- and O2-sparging experiments showed that dissolved oxygen inhibited the formation of manganese ions. These results together indicated that triplet excited species generated upon sunlight irradiation of methotrexate is the dominant factor for accelerating the reduction of MnO2 to manganese ions.
This study also observed that triplet excited species produced from methotrexate photolysis would react with dissolved oxygen to form superoxide anion (); next, will oxidize Mn2+ (generated from MnO2 reduction) into Mn3+ ions. Mn3+ has oxidizing ability and will further lead to methotrexate degradation. During sunlight photolysis alone, only 60% of methotrexate was degraded within 4 hours, while spiking Mn2+ into the solution would substantially enhance the methotrexate degradation (~100% degradation) under irradiation ([methotrexate]0 = 20 µM, [Mn2+]0 = 200 µM and pH0 = 3); however, after further addition of p-benzoquinone to scavenge , the degradation trend of methotrexate was similar to its photolysis alone. The results from this study indicated that methotrexate affects the photoredox reaction of MnO2 under sunlight irradiation. In addition to methotrexate, this work also provides insightful information for other self-photosensitized compounds and their environmental fate in natural water matrices.

並列關鍵字

Self-photosensitized compounds ； Manganese dioxides ； Simulated sunlight irradiation ； Methotrexate ； Triplet excited state ； Superoxide anion

參考文獻

Abolmaali, S.S., Tamaddon, A.M. and Dinarvand, R. (2013) A review of therapeutic challenges and achievements of methotrexate delivery systems for treatment of cancer and rheumatoid arthritis. Cancer Chemotherapy and Pharmacology 71(5), 1115-1130.

Aherne, G.W., English, J. and Marks, V. (1985) The role of immunoassay in the analysis of microcontaminants in water samples. Ecotoxicology and Environmental Safety 9(1), 79-83.

Andreozzi, R., Raffaele, M. and Nicklas, P. (2003) Pharmaceuticals in STP effluents and their solar photodegradation in aquatic environment. Chemosphere 50(10), 1319-1330.

Azuma, T., Otomo, K., Kunitou, M., Shimizu, M., Hosomaru, K., Mikata, S., Ishida, M., Hisamatsu, K., Yunoki, A., Mino, Y. and Hayashi, T. (2019) Environmental fate of pharmaceutical compounds and antimicrobial-resistant bacteria in hospital effluents, and contributions to pollutant loads in the surface waters in Japan. Science of the Total Environment 657, 476-484.

Ben, Y.J., Fu, C.X., Hu, M., Liu, L., Wong, M.H. and Zheng, C.M. (2019) Human health risk assessment of antibiotic resistance associated with antibiotic residues in the environment: A review. Environmental Research 169, 483-493.