Psoralen induces liver injury and affects hepatic bile acids metabolism in female and male C57BL/6J mice.

Psoralen is a major component of Fructus Psoraleae that could induce liver injury. In this study, C57BL/6J mice were administered with psoralen at doses of 80 mg/kg for 3, 7 and 14 days. Blood and liver samples were collected for serum biochemistry and histopathology examinations, respectively. Psoralen led to liver injury with significantly increased liver weight and liver coefficient and up regulated serum ALT, AST and TG but down regulated serum TC and TP. The expression of bile acid-associated transporters and enzymes was detected by western blot, and the results showed that psoralen significantly down-regulates the expressions of CYP7A1, CYP27A1, BSEP and OSTα protein while up-regulates the expressions of HMGCR and FASN, resulting in the obstacles of bile acid efflux in the liver. The contents of 24 kinds of bile acids in the liver were measured by LC-MS/MS, and the results showed that psoralen led to the accumulation of unconjugated bile acids in the liver, such as ALCA and CA, which were more severe in male mice than female mice. It was indicated that psoralen may disrupt the balance of bile acid metabolism by inhibiting the expression of the efflux transporter, which then leads to liver damage.

The changes of hepatic bile acid synthesis and transport and bile acids profiles in isopsoralen-induced liver injury C57BL/6J mice.

CONTEST: Isopsoralen, one of the main active and quality-control compounds in Psoralea corylifolia L. (Fabaceae), has antitumor and oestrogen-like effects. Previous studies demonstrated that isopsoralen induced hepatotoxicity and its long-term exposure led to cholestatic liver injury. OBJECTIVE: This study investigates the effect of three- or seven-day exposure of low dose isopsoralen (80 mg/kg) on bile acid homeostasis in C57BL/6J mice. MATERIALS AND METHODS: Forty-two C57BL/6J mice were randomly divided into control, three- and seven-day groups (n = 14 per group, half female and half male). Isopsoralen suspension was administrated intragastrically at 80 mg/kg once a day. Blood and liver samples were collected to measure biochemical indices and transport of BAs. The histopathology of the liver was also observed. HPLC-MS/MS was also used to measure the BAs profiles and transport activity. RESULTS: In the study, isopsoralen increased the levels of serum AST, ALT in three- and seven-day groups, and caused vacuolar degeneration and swelling in the liver. Canalicular efflux transporters BSEP, OSTα, MRP2, MRP3, and basolateral uptake transporters NTCP, OATP4 were inhibited after seven-day-administration. Moreover, amino acid binding enzymes (BAAT and BACS) were also inhibited after seven-day-administration. The composition of BAs changed greatly and the concentration of some unconjugated-BAs which have stronger hydrophobicity, such as CA, CDCA, was significantly increased. CONCLUSIONS: Isopsoralen (80 mg/kg) caused hepatotoxicity after short-term exposure by inhibiting the expression of efflux transporters, amino acid binding enzymes, and disrupting BAs spectrum.

Study on pharmacokinetics of eight active compounds from Bufei-Huoxue Capsule based on UHPLC-MS/MS.

Bufei-Huoxue Capsule (BFHX) was applied to treat chronic obstructive pulmonary disease (COPD) in China. It is composed of Astragali Radix, Paeoniae Radix Rubra, and Psoralea Fructus. A sensitive and reliable ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS/MS) method was developed and validated to quantify the eight main bioactive compounds (psoralen, isopsoralen, neobabaisoflavone, corylin, bavachin, astragaloside IV, ononin and formononetin) in rat plasma after oral administration of BFHX. Osthol was used as an internal standard (IS). Plasma samples were pretreated with methanol to precipitate protein. Chromatographic separation was accomplished using Hypersil GOLDTM C18 column (2.1 mm × 100 mm, 1.9 µm) with a gradient elution profile and a mobile phase consisting of (A) 0.1% formic acid in water and (B) acetonitrile and the flow rate was set at 0.2 mL/min. Multiple reaction monitoring (MRM) mode was applied to perform mass spectrometric analyses. All calibration curves were linear (r > 0.9908) in tested ranges. The intra- and inter-day accuracy and precisions of eight compounds at three different concentration levels were within the acceptable limits. The extraction recovery was within the range of 76.4 âˆ¼ 105.2% and the matrix effects were within the range of 88.3 âˆ¼ 115.0% (RSD ≤ 15.6%). The dilution effects were within the range of 90.2 âˆ¼ 114.9%. These 8 compounds were stable under the tested conditions. So the developed method was valid to evaluate the pharmacokinetic study of eight bioactive compounds after oral administration of BFHX.

Acetyl-α-boswellic acid and Acetyl-ß-boswellic acid protects against caerulein-induced pancreatitis via down-regulating MAPKs in mice.

This study is to investigate the protective effect of Acetyl-α-boswellic acid and Acetyl-ß-boswellic mixture(α/ß-ABA), which is the active ingredients isolated from Frankincense, on actue pancreatitis and its mechanism. Our experimental results showed that 2 µM α/ß-ABA reduced production of NO, TNF-α, IL-6, IL-10 and IL-1ß in RAW264.7 cells that were stimulated with lipopolysaccharide (LPS) which indicates its anti-inflammatory role. In pancreatitis model induced by caerulein, intra-gastrical administration of 100 mg/kg α/ß-ABA relieved inflammatory cells infiltration significantly and attenuated the serum elevation of amylase TNF-α and IL-6 remarkably in mice. Furthermore, α/ß-ABA down-regulated mitogen-activated protein kinase (MAPK) family phosphorylated proteins in pancreas, including phosphorylated p38, ERK1/2 and JNK, to reduce the serum inflammatory factors. Finally, α/ß-ABA alleviated the pancreatic edema and inflammatory cell infiltration in pancreatitis mice model. This study suggests that α/ß-ABA may be targeted for drug development against pancreatitis via modulating MAPKs pathway.