The kidneys are often involved in adverse effects and toxicity caused by exposure to foreign compounds, chemicals, and drugs. Early predictions of these influences are essential to facilitate new, safe drugs to enter the market. However, in current drug treatments, drug-induced nephrotoxicity accounts for 1/4 of reported serious adverse reactions, and 1/3 of them are attributable to antibiotics. Drug-induced nephrotoxicity is driven by multiple mechanisms, including altered glomerular hemodynamics, renal tubular cytotoxicity, inflammation, crystal nephropathy, and thrombotic microangiopathy. Although the functional proteins expressed by renal tubules that mediate drug sensitivity are well known, current in vitro 2D cell models do not faithfully replicate the morphology and intact renal tubule function, and therefore, they do not replicate in vivo nephrotoxicity. The kidney is delicate and complex, consisting of a filter unit and a tubular part, which together contain more than 20 different cell types. The tubular epithelium is highly polarized, and maintaining cellular polarity is essential for the optimal function and response to environmental signals. Cell polarity depends on the communication between cells, including paracrine and autocrine signals, as well as biomechanical and chemotaxis processes. These processes affect kidney cell proliferation, migration, and differentiation. For drug disposal research, the microenvironment is essential for predicting toxic reactions. This article reviews the mechanism of drug-induced kidney injury, the types of nephrotoxicity models (in vivo and in vitro models), and the research progress related to drug-induced nephrotoxicity in three-dimensional (3D) cellular culture models.

ObjectiveTo investigate the ability of Ganshuang granule (a liver-protecting drug widely used in clinical practice) extract to reduce N-acetyl-p-aminophenol (APAP)-induced hepatotoxicity and possible mechanisms. MethodsA total of five cell culture groups were set up in this experiment, i.e., normal control group, APAP injury group, and three injury protection groups treated with different concentrations of Ganshuang granule extract. Then 20 mmol/L APAP was added to the cell culture medium and incubated for 24 hours to establish an in vitro model of drug-induced liver injury, and the injury protection groups were treated with different concentrations of Ganshuang granule extract (0.2, 1, and 5 μg/ml) in advance for 8 hours of incubation before APAP were added for 24 hours. Related markers were measured, including the markers for hepatocellular injury ［alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH)］, the markers for mitochondrial injury ［mitochondrial membrane potential, and glutamate dehydrogenase (GDH)］, and antioxidant and oxidative stress markers ［glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA), and reactive oxygen species (ROS)］. Related mechanism was discussed based on the experimental results. A one-way analysis of variance was used for comparison of continuous data between multiple groups, and the least significant difference t-test was used for further comparison between two groups. ResultsGanshuang granule extract alleviated APAP-induced hepatotoxicity, improved cell viability (P＜0001), and reduced the levels of AST, ALT, and LDH in supernatant (P＜0.001, P＜0.001, and P＜0.05). Ganshuang granule extract inhibited APAP-induced hepatocellular oxidative stress, and compared with the APAP group, the Ganshuang granule extract groups had significant reductions in the oxidative stress indicators ROS and MDA (both P＜0.01). Ganshuang granule extract alleviated the loss of mitochondrial membrane potential induced by APAP (P＜0.05) and reduced the content of the mitochondrial injury marker GDH in supernatant (P＜0.001) in a dose-dependent manner. Ganshuang granule extract inhibited the expression of CYP2E1/1A2 (both P＜0.05) and increased the expression of phase Ⅱ enzymes in hepatocytes. Ganshuang granule extract induced the expression of Nrf2 and its downstream genes NQO-1 and GCLC (all P＜0.05). ConclusionGanshuang granule extract can prevent APAP-induced hepatocellular injury through two ways. The first way is that Ganshuang granule extract downregulates the expression of CYP2E1/1A2 and thus reduces the production of NAPQI, a toxic product of APAP; the second way is that Ganshuang granule extract upregulates the expression of the detoxification pathway, which can activate Nrf2 to increase the expression of antioxidant enzymes (SOD and GSH) and phase Ⅱ enzymes and thus accelerate the harmless metabolism of APAP.

药物性肝病又称药物性肝损伤,是我国非感染性肝病的第二大病种,美国肝衰竭/肝移植的首要原因.药物性肝损伤主要分为固有型肝损伤和非特异质型肝损伤.固有型药物性肝损伤在临床前安全研究中是无法被预测到的,而大多数药物引起的非特异质型肝毒性在临床前研究中就会被发现从而不会被应用到临床,但其中一个例外就是对乙酰氨基酚(扑热息痛,APAP),这种药物在治疗剂量之内是安全的,但是过量服用则会导致严重的肝损伤甚至急性肝衰竭.在欧美等发达国家,APAP过量服用是导致急性肝衰竭的主要原因.因此进一步阐明APAP引起肝损伤的细胞和分子机制,尤其是肝细胞死亡的机制,有助于尽早识别发生急性肝衰竭和不良预后的危险因素,从而有针对性的开发阻断肝损伤进程的治疗靶点与方案.