Hepatotoxicity induced by psoralen and isopsoralen from Fructus Psoraleae: Wistar rats are more vulnerable than ICR mice

Wang, Yu; Zhang, Hong; Jiang, Jizong; Zheng, Dan; Chen, Yuyu; Wan, Shi-Jie; Tan, Hongsheng; Tang, Liming; Hong, Xu

doi:10.1016/j.fct.2018.12.047

Cited by 41 publications

(26 citation statements)

References 33 publications

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“…However, several lines of previous researches indicated that psoralen caused hepatotoxicity after about 28 days or even longer time exposure at a mild dose in rats. 17,18 Our data suggested that psoralen might cause hepatotoxicity after administration for just 3 days at 60 mg/kg.…”

Section: Discussionmentioning

confidence: 70%

Effects of psoralen on hepatic bile acid transporters in rats

et al. 2020

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Fructus Psoraleae (FP), widely used in traditional medicine, is increasingly reported to cause serious hepatotoxicity in recent years. However, the main toxic constituents responsible for hepatotoxicity and the underlying mechanisms are poorly understood. In the present study, psoralen, a main and quality-control constituent of FP, was intragastrically administered to Sprague-Dawley rats at a dose of 60 mg/kg for 1, 3 and 7 days. Blood and selected tissue samples were collected and analyzed for biochemistry and histopathology to evaluate hepatotoxicity. The results showed that psoralen could induce hepatotoxicity by enhanced liver-to-body weight ratio and alterations of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total cholesterol after administration for 3 days. In addition, histopathological examinations also indicated the hepatotoxicity induced by psoralen. Furthermore, the mRNA and protein levels of hepatic bile acid transporters were significantly changed, in which MRP4, ABCG5 and ABCG8 were repressed, while the protein level of NTCP tended to increase in the rat liver. Taken together, psoralen caused liver injury possibly through affecting bile acid transporters, leading to the disorder of bile acid transport and accumulation in hepatocytes.

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Section: Discussionmentioning

confidence: 70%

Effects of psoralen on hepatic bile acid transporters in rats

et al. 2020

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“…Studies on Angelicae Pubescentis Radix suggest that the administration of a large dose of its extract may lead to cyanosis, agitated activity, and a quickened respiration in mice and may also have nephrotoxic effects (Lu et al, 2020). Psoralen and isopsoralen are the main toxic constituents of Psoraleae Fructus and both elicit toxic reactions in the rat liver when administered orally (80 and 40 mg/kg, respectively) (Wang et al, 2019c). These results indicate that BSHX decoction can exert cytotoxic effects in different organ systems, especially the respiratory system, liver, and kidney; however, we noticed that these side effects were highly dose-dependent.…”

Section: Discussionmentioning

confidence: 99%

Bu-Shen-Huo-Xue Decoction Ameliorates Diabetic Nephropathy by Inhibiting Rac1/PAK1/p38MAPK Signaling Pathway in High-Fat Diet/Streptozotocin-Induced Diabetic Mice

et al. 2020

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Diabetic nephropathy (DN), a leading cause of end-stage renal disease, is associated with high morbidity and mortality rates worldwide and the development of new drugs to treat DN is urgently required. Bu-Shen-Huo-Xue (BSHX) decoction is a traditional Chinese herbal formula, made according to traditional Chinese medicine (TCM) theory, and has been used clinically to treat DN. In the present study, we established a high-fat diet/streptozotocin-induced diabetic mouse model and treated the mice with BSHX decoction to verify its therapeutic effects in vivo. Ultraperformance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) was applied to analyze the chemical composition and active compounds of BSHX decoction. Markers of podocyte epithelial-mesenchymal transition and the Rac1/PAK1/p38MAPK signaling pathway were evaluated to investigate the mechanism underlying function of BSHX decoction. BSHX decoction effectively alleviated diabetic symptoms, according to analysis of the renal function indicators, serum creatinine, blood urea nitrogen, serum uric acid, and urinary albumin excretion rate, as well as renal histopathology and ultrastructural pathology of DN mice. We identified 67 compounds, including 20 likely active compounds, in BSHX decoction. The podocyte markers, nephrin and podocin, were down-regulated, while the mesenchymal markers, α-SMA and FSP-1, were up-regulated in DN mouse kidney; however, the changes in these markers were reversed on treatment with BSHX decoction. GTP-Rac1 was markedly overexpressed in DN mice and its levels were significantly decreased in response to BSHX decoction. Similarly, levels of p-PAK1 and p-p38MAPK which indicate Rac1 activation, were reduced on treatment with BSHX decoction. Together, our data demonstrated that BSHX decoction ameliorated renal function and podocyte epithelial-mesenchymal transition via inhibiting Rac1/PAK1/p38MAPK signaling pathway in high-fat diet/streptozotocin-induced diabetic mice. Further, we generated a quality control standard and numerous potential active compounds from BSHX decoction for DN.

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“…These results suggested that psoralen injured the visceral organs more seriously than isopsoralen, and maybe make more contribution to the liver injury induced by Fructus Psoraleae . In the previous studies about the acute hepatotoxicity of psoralen and isopsoralen [22], high dosage are usually used and the toxic reactions occurred quickly and severely, which probably mask the underlying differences of the two ingredients that induced toxic reactions. Our findings imply that the chronic and cumulative toxicity caused by psoralen or isopsoralen can be delayed [23] for 3 months to be appear after administration.…”

Section: Discussionmentioning

confidence: 99%

Long-Term Exposure of Psoralen and Isopsoralen Induced Hepatotoxicity and Serum Metabolites Profiles Changes in Female Rats

Wang

et al. 2019

Metabolites

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Pre-clinical safety evaluation of traditional medicines is imperative because of the universality of drug-induced adverse reactions. Psoralen and isopsoralen are the major active molecules and quality-control components of a traditional herbal medicine which is popularly used in Asia, Fructus Psoraleae. The purpose of this study is to assess the long-term effects of psoralen and isopsoralen with low levels on the biochemical parameters and metabolic profiles of rats. Three doses (14, 28, and 56 mg/kg) of psoralen and one dose (28 mg/kg) of isopsoralen were administered to rats over 12 weeks. Blood and selected tissue samples were collected and analyzed for hematology, serum biochemistry, and histopathology. Metabolic changes in serum samples were detected via proton nuclear magnetic resonance (1H-NMR) spectroscopy. We found that psoralen significantly changed the visceral coefficients, blood biochemical parameters, and histopathology, and isopsoralen extra influenced the hematological index. Moreover, psoralen induced remarkable elevations of forvaline, isoleucine, isobutyrate, alanine, acetone, pyruvate, glutamine, citrate, unsaturated lipids, choline, creatine, phenylalanine, and 4-hydroxybenzoate, and significant reductions of ethanol and dimethyl sulfone. Isopsoralen only induced a few remarkable changes of metabolites. These results suggest that chronic exposure to low-level of psoralen causes a disturbance in alanine metabolism, glutamate metabolism, urea cycle, glucose-alanine cycle, ammonia recycling, glycine, and serine metabolism pathways. Psoralen and isopsoralen showed different toxicity characteristics to the rats.

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Hepatotoxicity induced by psoralen and isopsoralen from Fructus Psoraleae: Wistar rats are more vulnerable than ICR mice

Cited by 41 publications

References 33 publications

Effects of psoralen on hepatic bile acid transporters in rats

Effects of psoralen on hepatic bile acid transporters in rats

Bu-Shen-Huo-Xue Decoction Ameliorates Diabetic Nephropathy by Inhibiting Rac1/PAK1/p38MAPK Signaling Pathway in High-Fat Diet/Streptozotocin-Induced Diabetic Mice

Long-Term Exposure of Psoralen and Isopsoralen Induced Hepatotoxicity and Serum Metabolites Profiles Changes in Female Rats

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