文献翻译19 drug-induced kidney injury(DIKI)
The kidney is particularly susceptible to drug injury because of its high share of cardiac output and its role in excretion of waste compounds from the body. drug-induced kidney injury (DIKI) is a relatively common clinical condition, particularly in critical care settings caused by acute kidney injury (AKI). Up to 30% of all critically ill patients develop AKI with nearly 6% of those diagnosed requiring subsequent kidney replacement therapy. Despite this, only a fraction (2%) of drug candidates are rejected due to nephrotoxicity in early (phase I) clinical studies.This can be caused by species to species translation issues such as drug-metabolising enzyme (cytochrome P450; CYP) expression and individual differences in clearance performance.
参考答案：肾脏特别容易受到药物损伤，因为它在心输出量中所占的比例很高，并且在排泄体内的废物化合物时发挥作用。药物性肾损伤（DIKI）是一种相对常见的临床疾病，尤其是在由急性肾损伤（AKI）引起的重症监护环境中。高达30%的危重病患者发生急性肾损伤，近6%的确诊患者需要后续肾脏替代治疗。尽管如此，在早期（I期）临床研究中，只有一小部分（2%）候选药物因肾毒性而被拒绝。这可能是由物种间的(基因)翻译问题引起的，如药物代谢酶（细胞色素P450；CYP）的表达和清除能力的个体差异。
The kidneys utilize roughly 10% of the body’s oxygen supply to produce the energy required for accomplishing their primary function: the regulation of body fluid composition through secreting, filtering, and reabsorbing metabolites and nutrients. To ensure an adequate ATP supply, the kidneys are particularly enriched in mitochondria.Transporters are driven by the ion electrochemical gradients and the membrane potential generated by the asymmetric transport of ions across the plasma membrane mediated by the ATPase pumps. these transporters are highly expressed on the proximal tubular cell membranes and happen to also transport drugs whose levels in the proximal tubular cells can rapidly rise, thereby damaging the mitochondria and resulting in cell death and kidney injury.
参考答案：肾脏利用人体约10%的氧气供应来产生完成其主要功能所需的能量:通过分泌、过滤和再吸收代谢物和营养物质来调节体液成分。为了保证ATP的充足供应，肾脏的线粒体特别丰富。转运体由离子电化学梯度和由ATP酶泵介导的离子跨膜的不对称转运所产生的膜电位驱动。这些转运蛋白在近端小管细胞膜上高度表达，并碰巧也转运药物，药物在近端小管细胞中的水平可迅速上升，从而破坏线粒体，导致细胞死亡和肾脏损伤。
文献翻译20 drug-induced liver injury(DILI)
drug-induced liver injury (DILI) is initiated by the parent xenobiotic or its associated metabolites causing unanticipated damage either to hepatocytes or the non-parenchymal cells of the liver. Acetaminophen (APAP),a kind of analgesic/antipyretic medication,is rapidly absorbed in the gut and is transferred to the liver where it is metabolized mainly by phase II conjugation reactions and only a minor fraction is oxidized by CYPs, especially CYP2E1. However, an overdose can overwhelm the capacity of the conjugation pathways resulting in a greater percentage of APAP being metabolized by CYP2E1 which forms the highly reactive electrophile, N-acetyl -parabenzoquinone imine (NAPQI,N-乙酰-对苯醌亚胺). NAPQI will readily conjugate with sulfhydryl groups. Conjugation with GSH can be a safe detoxification, however, at significantly high doses of APAP the increased levels of NAPQI will lead to a depletion of hepatic GSH.
参考答案：药物性肝损伤(DILI)是由外源性原型化合物或其相关代谢物引起的对肝细胞或肝脏非实质细胞的意外损伤。对乙酰氨基酚(Acetaminophen, APAP)是一种镇痛/解热药物，在肠道内被迅速吸收，并转移到肝脏，在肝脏主要通过II相结合反应进行代谢，只有一小部分被细胞色素酶(CYPs)氧化，尤其是CYP2E1。然而，过量的对乙酰氨基酚可能会使结合反应途径过载(注：这里过载可意译为饱和)，导致APAP被CYP2E1代谢的比例更大，形成高度活性的亲电试剂，N-乙酰基-对苯醌亚胺(NAPQI)。NAPQI很容易与巯基结合。还原型谷胱甘肽结合可能是一种安全的解毒方法，然而，在APAP显著高剂量时，NAPQI水平的增加将导致肝脏还原型谷胱甘肽的消耗。
drug-induced liver injury (DILI) due to chemotherapeutic drugs is a significant cause of morbidity and mortality.The major mechanisms underlying chemotherapyrelated hepatotoxicity are based on the production of reactive metabolites generated by phase I oxidation reactions, immunological injury, or alterations in mitochondrial function. Underlying liver disease and hepatic involvement by tumor are important modifiers of liver injury, and reversibility is not universal after drug cessation. Chemotherapy can also exacerbate underlying liver disease, particularly hepatitis B, leading to worsening hepatic function. Diagnosing DILI due to chemotherapeutic agents is particularly challenging because competing etiologies, such as hepatotoxicity from other medications, opportunistic infections, radiation therapy, and pre-existing liver disease, are frequent.
参考答案：由化疗药物引起的药物性肝损伤是化疗发病率和死亡率的重要原因。化疗相关肝毒性的主要机制是基于I期氧化反应、免疫损伤或线粒体功能改变产生的活性代谢物。潜在的肝病和肝癌是肝损伤的重要调节因素，停药后的可逆性并不普遍。化疗也会加重潜在的肝脏疾病，特别是乙型肝炎，导致肝功能恶化。由于其他药物引起的肝毒性、机会性感染、放疗和预先存在的肝脏疾病等常见的竞争性病因，诊断化疗药物引起的药物性肝损伤尤其具有挑战性。