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自2019年12月首次发现新型冠状病毒(COVID-19)以来,新冠肺炎在全球范围内迅速传播,对人类健康和经济发展构成严重威胁。为了防止疫情的进一步恶化,我国筛选出针对COVID-19的抗病毒药物(antiviral drug,ATVs)并投入临床治疗。中国科学院在2020年初的研究中发现,新型冠状病毒已发生突变,突变后的病毒具有更强的感染性和侵略性[1]。近日,世界各地也不断出现有关新冠病毒变异的报道,病毒变异已成为人们关注的焦点。在英国、南非、美国、澳大利亚、日本、中国等几十个国家都相继发现了引发感染的新冠病毒变异株。很多病毒学专家认为COVID-19有可能转成慢性疾病,像流感一样与人类共存。因此,世界各国纷纷启动相关ATVs的研发和筛选,ATVs的需求和使用也在激增。此外,由于病毒性流感的频发以及部分地区医疗水平落后引起HIV病毒的传播,导致抗流感药物、抗HIV病毒药物等ATVs被广泛应用,这些ATVs所带来的生态环境问题同样不容小觑[2]。
ATVs属于药品及个人护理品(PPCPs),它通过阻止病毒复制,缩短疾病时间[3]。根据作用机制,ATVs大致可分为5类:抗流感病毒药物、抗疱疹病毒药物、抗巨细胞病毒药物、抗肝炎病毒药物和抗HIV病毒药物[4]。抗流感病毒药物又分为,以金刚烷胺和金刚乙胺为代表,通过M2离子通道抑制剂[4]阻断甲型流感病毒M2蛋白[5]。以奥司他韦和扎那米韦为代表,通过神经氨酸酶抑制剂特异性结合神经氨酸酶的活性部位,引起酶失活[5]。以利巴韦林为代表的广谱型病毒药物,通过抑制肌苷单磷酸脱氢酶阻断鸟苷一磷酸的合成。阿比多尔为代表的干扰素诱导药物阻断宿主细胞与病毒脂膜的融合。主要的抗疱疹病毒药物是广谱抗疱疹病毒药物阿昔洛韦,以及伐昔洛韦和喷昔洛韦衍生物,它们通过与病毒DNA聚合酶竞争来阻断病毒DNA合成[6]。常见的抗巨细胞病毒药物有能抑制脱氧鸟苷三磷酸与病毒DNA结合的更昔洛韦、能选择性抑制二磷酸与病毒DNA聚合酶结合的磷酸和能竞争性抑制DNA聚合酶中断DNA合成的西多福韦[7]。抗肝炎病毒药物包含干扰素和核苷酸类似物,干扰素可分为α(白细胞)型、β(成纤维细胞)型、γ(淋巴细胞)型,可起到免疫调节、抗病毒以及抗增殖的作用,它们是由病毒和诱生剂对生物体细胞作用下产生的分泌蛋白;核苷酸类似物中包含胞嘧啶核苷类似物恩典他滨,它的抗肝炎病毒活性为拉米夫定的4—10倍[8],以及用于乙型肝炎治疗的阿德福韦酯[9]和恩替卡韦[10]。医学中使用到的抗HIV病毒药物有3种,分别为HIV反转录酶抑制剂、HIV蛋白抑制药和融合蛋白抑制药,其中HIV反转录酶抑制剂包含核苷类药物齐多夫定和非核苷类反转录酶抑制剂地拉韦定。HIV蛋白抑制药包括可竞争性抑制或互补蛋白酶活性位点的沙奎那韦、利托那韦和奈非那韦等[11]。T20为最早医用的融合蛋白抑制药可将病毒阻断在感染源头[12]。
ATVs跟大多数药品一样很难被人体完全吸收,会以代谢物或原型经由有机体排泄物排出。通常情况下其在水体环境中的污染浓度很低,只处于ng·L−1的数量级[13]。但是,由于一些ATVs的使用量大,通过水系统进入人体,持续的输入产生假持续现象,它在水体或生物体中的富集效应会对生态环境造成影响。2008年Duffy[14]等已经发现,ATVs会存在于水体环境中。近年来的研究表明,中国、美国、意大利、西班牙等许多国家的水环境中都存在大量有毒的ATVs及其反应产生的二次产物。一般来说,中间产物的毒性会比最初的ATVs更大[15]。因为ATVs长期存留在自然水体中难以去除,甚至有引发病毒抗性的环境风险。然而,这些ATVs在水环境中的迁移转化以及对水生生态系统的毒性作用尚不清楚。在COVID-19爆发的情况下,人体排泄的ATVs在水环境中的环境行为及其可能产生的生物毒性效应不容忽视。
本文首先将对ATVs在水环境中污染现状、环境行为、毒性效应以及风险评估进行详细的综述,其次收集了全球不同区域水体中ATVs数据信息,并分析ATVs在水环境中所呈现的污染水平,最后评估了ATVs进入水环境后带来病毒耐药性的生态风险,为水环境中ATVs的迁移转化和归趋、水污染防治及水生态环境风险评价提供理论依据。
抗病毒药物在水环境中的污染现状及环境归趋
Pollution status and environment trend of antiviral drugs in water environment
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摘要: 禽流感、埃博拉、HIV等病毒的传播也使得对抗病毒药物(ATVs)的消费量的增加,这些药物进入水体后将产生严峻的水环境污染和病毒耐药性问题。本文对ATVs在水环境中的污染现状、环境行为、毒性效应,以及生态风险评估研究状况进行了综述。中国、日本、德国等已针对亚洲、欧洲水环境中ATVs含量展开研究,美国等国家仅在流感大流行后评估了奥司他韦等ATVs对水环境造成的影响;在水环境中被检出频率最高的ATVs为法匹拉韦、奥司他韦、利巴韦林和奥司他韦羧酸盐;在含量上水环境中ATVs浓度多处于ng·L−1;中国珠江三角洲地区水环境中奥司他韦、利巴韦林和奥司他韦羧酸盐等常见ATVs均低于检出限;在空间分布上,非洲国家等不发达地区水环境中的ATVs含量高于发达国家,目前检出的中国水环境中ATVs含量低于非洲、欧洲、日本等地区和国家。ATVs在水环境中易发生光化学反应产生光致毒性,对水中的植物、大型溞和鱼类具有一定的毒性,对人体可造成致畸、致癌和致突变的毒性效应,引导病毒产生耐药性。对ATVs的风险评估研究表明,ATVs的生态风险较高,相关部门应重视对水环境中这类污染物的净化去除。最后,本文提出全面防控水环境中ATVs污染的建议,以期为ATVs水污染防治及水生态环境风险评价提供理论基础。Abstract: The global epidemic of new coronavirus pneumonia (COVID-19) has promoted a surge in related antiviral drugs (ATVs) use.The spread of avian influenza, Ebola virus, HIV and other viruses has also increased the consumption of ATVs, which will cause serious water pollution and virus resistance. The pollution status, environmental behaviors and toxic effects of ATVs in water environment were reviewed in detail, and the risk assessment was summarized in this paper. China, Japan and Germany have studied ATVs in water environment in Asia and Europe, while the United States only evaluated the impact of ATVs such as oseltamivir after the influenza pandemic. It has found that the most frequently detected ATVs include faraway, oseltamivir, ribavirin and oseltamivir carboxylate. The concentration of ATVs was mostly ng·L−1 in the water environment. The ATVs content in less developed regions such as African countries is higher than that in developed countries. The content of common ATVs such as oseltamivir, ribavirin and oseltamivir carboxylate in the Pearl River Delta of China were under the detection limit, and is lower than that in Africa, Europe and Japan. ATVs are prone to photochemical reactions in water environment, thus producing phototoxicity, which are toxic to plants, daphnia magna and fish in the water, causing teratogenic, carcinogenic and mutagenic toxic effects to human body, and guide the virus to develop drug resistance. The research on risk assessment of ATVs showed that ATVs have high ecological risks. Thus relevant departments should pay attention to the purification and removal of such pollutants in water environment. This paper put forward suggestions for the comprehensive prevention and control of ATVs pollution in water environment, so that could provide theoretical basis for ATVS water pollution prevention, control and water ecological environment risk assessment.
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Key words:
- antiviral drugs /
- pollution status /
- environmental behavior /
- toxic effects /
- risk assessment
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表 1 全球各地水域ATVs检测统计
Table 1. Antiviral drugs detection statistics in waters around the world
地区
AreaATVs种类
Types of antiviral drugsATVs浓度/(ng·L−1)
Concentration of antiviral drugs文献
Reference德国里德河 阿昔洛韦 1.00 [13] 德国里德河 阿巴卡韦 <LOQ(0.20) [13] 德国里德河 拉米夫定 10.00 [13] 德国里德河 奈韦拉平 1.00 [13] 德国里德河 奥司他韦 0.20 [13] 德国里德河 奥司他韦羧酸盐 0.20 [13] 德国里德河 喷昔洛韦 1.00 [13] 德国里德河 利巴韦林 4.00 [13] 德国里德河 司他夫定 1.00 [13] 德国里德河 齐多夫定 1.00 [13] 德国内卡 阿巴卡韦 <LOQ(5.00) [19] 德国韦施尼茨 阿巴卡韦 <LOQ(5.00) [19] 德国莫道 阿巴卡韦 <LOQ(5.00) [19] 德国施瓦茨巴赫 阿巴卡韦 <LOQ(5.00) [19] 德国罗道 阿巴卡韦 <LOQ(5.00) [19] 德国美因河 阿巴卡韦 <LOQ(5.00) [19] 德国拉赫 阿巴卡韦 <LOQ(5.00) [19] 德国拉恩 阿巴卡韦 <LOQ(5.00) [19] 德国莱茵河 阿巴卡韦 <LOQ(5.00) [19] 南非 扎西他滨 36.00 [22] 南非 替诺福韦 192.0 [22] 南非 拉米夫定 160.00 [22] 南非 地高辛 54.10 [22] 南非 司他夫定 431.00 [22] 南非 阿巴卡韦 n.q [22] 南非 齐多夫定 319.00 [22] 南非 奈韦拉平 360.00 [22] 南非 茚地那韦 n.q [22] 南非 利托那韦 n.q [22] 南非 洛匹那韦 239.00 [22] 南非 依法韦伦 n.q [22] 肯尼亚WWTPs1 拉米夫定 76000 [23] 肯尼亚WWTPs2 奈韦拉平 53700 [23] 肯尼亚WWTPs3 齐多夫定 847100 [23] 肯尼亚WWTPs1 拉米夫定 1300 [23] 肯尼亚WWTPs2 奈韦拉平 700 [23] 肯尼亚WWTPs3 齐多夫定 47300 [23] 肯尼亚WWTPs1 拉米夫定 322000 [23] 肯尼亚WWTPs2 奈韦拉平 481000 [23] 肯尼亚WWTPs3 齐多夫定 301000 [23] 日本淀川河 奥司他韦 20.00 [15] 日本淀川河 培拉米韦 10.00 [15] 日本淀川河 扎那米韦 89.00 [15] 日本淀川河 奥司他韦羧酸盐 70.00 [15] 波兰 达芦那韦 169.00(Max) [27] 美国 拉米夫定 4.00(Min) [30] 美国 阿巴卡韦 n.q [30] 美国 阿昔洛韦 12.00 [30] 美国 奥塞米韦 n.q [30] 美国 奈韦拉平 n.q [30] 芬兰派廷奈河 奈韦拉平 n.q [32] 肯尼亚内罗毕河 奈韦拉平 4859.00(Max) [32] 肯尼亚马萨瑞河 奈韦拉平 300.00(Max) [24] 法国 阿巴卡韦 2.60±1.70(Max) [25] 法国 拉米夫定 4.10±2.50(Max) [25] 法国 拉米夫定 0.80—2.60 [25] 法国 奈韦拉平 n.q [25] 法国 奈韦拉平 0.20—0.50 [25] 法国 利托那韦 12.00±5.00 [25] 法国 利托那韦 <LOQ(0.20) [25] 法国 齐多夫定 33.00±27.00 [25] 悉尼水域 奥司他韦 1.29 [28] 西班牙埃布罗河 奥司他韦 50.00 [31] 西班牙埃布罗河 奥司他韦 100.00 [31] 中国珠江三角洲 阿昔洛韦 <LOQ(6.00) [33] 中国珠江三角洲 更昔洛韦 <LOQ(9.00) [33] 中国珠江三角洲 奥司他韦 <LOQ(3.00) [33] 中国珠江三角洲 奥司他韦羧酸盐 <LOQ(5.00) [33] 中国珠江三角洲 利巴韦林 <LOQ(74.00) [33] 中国珠江三角洲 司他夫定 <LOQ(7.00) [33] 中国珠江三角洲 齐多夫定 <LOQ(7.00) [33] 中国长江三角洲 金刚烷胺 351.00(Max) [33] 注:n.q-Not quantified;Max-Maximum detection volume;Min-Minimum detection volume;LOQ - Minimum quantitation limit;WWTPs - Waste Water Treatment Plants. 表 2 法匹拉韦、奥司他韦、利巴韦林和奥司他韦羧酸盐的理化信息
Table 2. Physical and chemical information of chloroquine phosphate,ribavirin,remdesivir and fapilavir
化合物
Compound分子式
Molecular formulaCAS No. 分子结构
Molecular
Structure分子量
Molecular weight溶解度
Solubility正辛醇/水分配系数
lgKow酸度系数
pKa法匹拉韦
FavipiravirC5H4FN3O2 259793-96-9 157.1 22.85 −0.96 8.77±0.60 奥司他韦
OseltamivirC16H28N2O4 196618−13-0 312.40 159.2 0.95 7.7±1.1 利巴韦林
RibavirinC8H12N4O5 36791-04-5 244.20 ≥100 −2.03 12.95±0.70 奥司他韦羧酸盐
Oseltamivir carboxylate
hydrochlorideC14H25ClN2O4 1415963-60-8 320.81 52.38 0.18 — -
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