Chemical induction of hepatic apoptosis in rodents

The urge of identifying new pharmacological interventions to prevent or attenuate liver injury is of critical importance and needs an expanded experimental toolbox. Hepatocyte injury and cellular death is a prominent feature behind the pathology of liver diseases. Several research activities focused on identifying chemicals and hepatotoxicants that induce cell death by apoptosis, in addition to presenting its corresponding signaling pathway. Although such efforts provided further understanding of the mechanisms of cell death, it has also raised confusion concerning identifying the involvement of several modes of cell death including apoptosis, necrosis and fibrosis. The current review highlights the ability of several chemicals and potential hepatotoxicants to induce liver damage in rodents by means of apoptosis while the probable involvement of other modes of cell death is also exposed. Thus, several chemical substances including hepatotoxins, mycotoxins, hyperglycemia inducers, metallic nanoparticles and immunosuppressant drugs are reviewed to explore the hepatic cytotoxic spectrum they could exert on hepatocytes of rodents. In addition, the current review address the mechanism by which hepatotoxicity is initiated in hepatocytes in different rodents aiding the researcher in choosing the right animal model for a better research outcome.     

Prediction of clinically relevant drug‐induced liver injury from structure using machine learning

Drug‐induced liver injury (DILI) is the most common cause of acute liver failure and often responsible for drug withdrawals from the market. Clinical manifestations vary, and toxicity may or may not appear dose‐dependent. We present several machine‐learning models (decision tree induction, k‐nearest neighbor, support vector machines, artificial neural networks) for the prediction of clinically relevant DILI based solely on drug structure, with data taken from published DILI cases. Our models achieved corrected classification rates of up to 89%. We also studied the association of a drug's interaction with carriers, enzymes and transporters, and the relationship of defined daily doses with hepatotoxicity. The results presented here are useful as a screening tool both in a clinical setting in the assessment of DILI as well as in the early stages of drug development to rule out potentially hepatotoxic candidates.     

Can acetaminophen/dimethyl sulfoxide formulation prevent accidental and intentional acetaminophen hepatotoxicity?

An overdose of acetaminophen (APAP) causes liver injury in experimental animals and humans. The activation step (formation of reactive metabolite, N-acetyl-p-benzoquinone imine by cytochrome P450 system) and the consequent downstream pathway of oxidative stress, nitrosative stress, and inflammation play an important role in APAP-induced hepatotoxicity. Formulation of APAP with an inhibitor of the activation step would be ideal to prevent accidental and intentional APAP toxicity. Dimethyl sulfoxide (DMSO) is a common colorless, inexpensive solvent, and considered safe in human. We hypothesized that a less hepatotoxic APAP if co-formulated with DMSO. To test this hypothesis, C57BL/6 mice were given toxic dose of APAP (250 mg kg⁻¹, i.p.) mixed with different doses of DMSO (25, 50, 100, and 200 μl kg⁻¹). Six hours after APAP treatment, blood and lives were collected for analysis. In DMSO treated groups, there was dose-dependent decrease in markers of liver injury, alanine aminotransferase, and aspartate aminotransferase. Maximum protection was obtained with 200 μl DMSO kg⁻¹. DMSO was shown to inhibit the activation step by decreasing the rate of GSH depletion in vivo and inhibiting cytochrome P450 system in vitro. Also the levels of lipid peroxides, nitrate/nitrite, tumor necrosis factor-alpha, and interleukin 1β were decreased significantly. In conclusion, DMSO exerts its protective action by inhibiting the metabolic activation of APAP and thus alleviating the downstream, oxidative stress, nitrosative stress, and inflammation via indirect inhibition. Our findings suggest that replacing the current APAP with APAP/DMSO formulation could prevent accidental and intentional APAP toxicity.     

HIV／TB病人抗结核治疗强化期发生药物性肝炎的研究

目的了解广西地区人类免疫缺陷病毒（HIV）及结核（TB）双重感染病人（HIV／TB病人）,在标化抗结核治疗强化期药物性肝炎的发生情况,分析发生药物性肝炎的影响因素。方法以同期HIV阴性的TB病人作对照,选择16个可能对发生药物性肝炎产生影响的因素进行Spearman相关性分析,对单因素分析有统计学意义的影响因素进行Logistic回归模型多因素分析。结果符合观察条件的HIV／TB病人共369例,药物性肝炎发生率为22．8％（84例）;HIV阴性的TB共350例,药物性肝炎发生率为13．1％（46例）,两组比较差异有统计学意义（Pd0．001）。HIV／TB组治疗失败47例,其中与药物性肝炎相关占63．8％。单因素分析HIV／TB病人药物性肝炎的危险因素为女性、体质量减少、合并乙型肝炎病毒（HBV）或／和丙型肝炎病毒（HCV）感染、既往有肝损伤病史、血清蛋白降低、低CD4^＋T淋巴细胞计数、静脉途径用药、用药后嗜酸性粒细胞计数升高;多因素分析显示：体质量减少、既往有肝损伤病史、低CD4^＋T淋巴细胞计数、静脉用药、用药后嗜酸性粒细胞计数升高,是导致药物性肝炎的危险因素。结论HIV／TB病人抗结核治疗易出现药物性肝炎,对预后影响大;HIV感染后体质下降和免疫异常是导致药物性肝炎发生率高的主要原因。     

Protective effect of trapidil and l-arginine against renal and hepatic toxicity induced by cyclosporine in rats

Rationale: Cyclosporine A (CsA) leads to renal and liver injury, production of free radicals and nitric oxide (NO) deficiency. This study investigates the possible protective effects of trapidil and l-arginine against CsA-induced tissue injury. Objectives: Forty adult male Wistar rats (180 ± 20 g) were divided into five groups, eight animals in each. The first group served as control, second group served as CsA group, third group served as CsA + trapidil group, fourth group served as CsA + l-arginine group, and fifth group served as CsA + trapidil + l-arginine group. Kidney and liver functions, inflammatory mediators, cytokines, oxidant and antioxidant parameters as well as histopathological studies of renal and liver tissue were assessed in all groups. Main findings: CsA induced renal and hepatic dysfunction, which was confirmed by laboratory and histopathological examination. Administration of trapidil diminished the renal and liver injury and significantly attenuated the levels of serum creatinine, urea, aspartate aminotransferase (AST), alanine aminotransferase (ALT), interleukin-1β (IL-1β), tumor necrosis factor alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and oxidative stress, while it significantly elevated the level of serum nitric oxide and the activity of antioxidative stress. l-Arginine gave the same trend as trapidil, but trapidil effect was more pronounced. Coadministration of trapidil + l-arginine significantly ameliorated the toxic effect of CsA, but did not differ significantly from the effect of trapidil alone. Conclusions: Treatment with trapidil or l-arginine diminished the renal and hepatic CsA-induced toxicity. However, the effect of trapidil was more pronounced. Therefore, treatment with trapidil alone may be the most economic and effective as a potential therapeutic agent in CsA injury.     

雷公藤多苷肝毒性发生机制及减毒相关研究进展

雷公藤多苷是一种从植物雷公藤中提取出的有效组分,具有免疫抑制、抗炎等作用,临床上多用于治疗风湿性关节炎和肾病综合征等。在雷公藤多苷众多不良反应中,其肝脏相关不良反应尤为显著。针对雷公藤多苷的肝毒性作用,总结近十年对雷公藤多苷肝毒性作用及机制的研究进展,并对其毒性物质基础进行了分析,对相应的配伍减毒药物以及其保护机制进行了总结分析,为雷公藤多苷的临床合理使用及配伍减毒提供文献和理论依据。     

Identification and analysis of the reactive metabolites related to the hepatotoxicity of safrole

1.?Safrole is the main component of the volatile oil in Xixin, which has a strong antifungal effect. However, safrole has been shown to be associated with the development of hepatocellular carcinoma. Methylenedioxyphenyl and allyl-benzene substructures of safrole may cause a mechanism-based inhibition (MBI) of CYP450 enzymes (CYPs) and produce reactive metabolites (RMs), resulting in inhibition of enzyme activity and toxic effects.

2.?Based on the experiments of CYPs cocktail screening, glutathione (GSH) capture and the IC₅₀ data, we found that safrole had an inhibitory effect on CYP1A2. The test of enzyme activity recovery when adding GSH may help to verify the MBI of safrole.

3.?Two metabolites, 1,2-dihydroxy-4-allylbenzene (M1) and 1′-hydroxy safrole (M2) could be captured by GSH. The ultra performance liquid chromatography - tandem mass spectrometer (UPLC-MS/MS) method was used to identify the RMs through a detailed characterization of the safrole cleavage processes and the GSH-M1 adduct. The RMs identified are quinone and its tautomer. Thus, preliminary conclusion can be obtained that safrole is a mechanism-based inhibitor of CYP1A2.

4.?The cleavage process of the GSH-M1/M2 adduct was analyzed in further detail. We believe the safrole hepatotoxicity mechanism is related to the RMs mediated by CYP1A2. This work provides important information on predicting in vivo drug induced liver injury.