The mechanism of Psoralen and Isopsoralen hepatotoxicity as revealed by hepatic gene expression profiling in SD rats

Abstract

Background The main bioactive components of Fructus psoraleae, such as psoralen and isopsoralen, are known to be hepatotoxic. However, its underlying mechanism is to be elucidated. Methods To address this, SD rats were randomly divided into control group, 60 mg/kg psoralen group and 60 mg/kg isopsoralen group. Blood was collected to detect serum biochemical indices. RNA was extracted from liver samples, and then, cDNA gene expression profiles were analysed. Results Psoralen administration significantly up‐regulated serum AST (aspartate aminotransferase) while addition of isopsoralen increased serum ALT (alanine aminotransferase), AST, TBA (total bile acid) and TG (total triglyceride) levels. A total of 172 differentially expressed genes (DEGs) were acquired between psoralen group and control group while 884 DEGs were screened between isopsoralen group and control group. Chemical Carcinogenesis and Metabolism of Xenobiotics by Cytochrome P450 were the two most significantly enriched pathways as revealed by DEGs. Liver was the most impacted organ, and endoplasmic reticulum was the most impacted organelle in subcellular level. Finally, some kinds of cancers and cytochrome p450 oxidoreductase deficiency were predicted. Taken together, psoralen and isopsoralen might cause hepatotoxicity mainly through cytochrome P450 metabolism of xenobiotics. Furthermore, Cyp1a1, Cyp1a2, Gstm1 and Akr7a3 worked as key genes in hepatotoxicity. Moreover, endoplasmic reticulum was the main target subcellular structure in hepatotoxicity induced by psoralen and isopsoralen.

The Accumulation of Psoralen Contributes to Its Hepatotoxicity Revealed by Pharmacokinetic and Toxicokinetic Study after Repeated Administration

“…Psoralen was deemed to be innoxious at low doses in previous publications. 30,31 Also, a recent clinical study reported that low-dose and low-frequency oral psoralen−UV-A treatment are effective to treat early-stage mycosis fungoides. 32 However, other reports suggested that the effect of drug accumulation in the body should not be ignored.…”

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

“…The results inspired us that the long-term exposure might induce accumulated psoralen in the body and injure metabolic enzymes. We have previously found that psoralen and isopsoralen injured the liver through dislocating the cytochrome P450 metabolism [25], which maybe the main targets of psoralen and isopsoralen in the body. However, in the recovery period, all the damage were abolished except for the increases of AST (14 mg/kg, P < 0.05) and BUN (14 and 28 mg/kg, P < 0.01 and P < 0.05, respectively).…”

A Review of the Pharmacological Properties of Psoralen

“…Song et al found that psoralen may induce liver injury in rats through the cytochrome P450 metabolic pathway of xenobiotics, among which Akr7a3, Gstm1, Cyp1a2, and Cyp1a1 are important genes in hepatotoxicity, and the endoplasmic reticulum is the principal target subcellular structure. It has been suggested that various cancers and metabolic conditions might be susceptible to hepatotoxicity induced by psoralen (Song et al, 2019). Wang et al demonstrated that psoralen inhibited the activity and protein expression of CYP2E1 (Wang et al, 2012).…”