Rhein alleviates pancreatitis but induces hepatotoxicity via macrophage activation

Rhubarb, a traditional Chinese medicine with potent purgative effects, is commonly used in treating acute pancreatitis in China. Rhein is one of the main active components of total anthraquinones in Rhubarb and has been reported to exert protective effects on pancreatitis. However, there is a potential risk of liver toxicity when Rhein is not used properly.

To investigate the effects of rhein on pancreatitis and related liver injury and the key roles of macrophages.

Acute pancreatitis was induced by continuous intraperitoneal injection of caerulein. Hematoxylin-eosin staining was used to evaluate the histopathological characteristics. The macrophages were cleared by intraperitoneal injection of clodronate liposomes (CL). The secretions of various cytokines were detected by protein microarray or ELISA. Normal mouse hepatocytes (AML12) were stimulated by macrophage conditioned medium (CM) or single cytokine such as TNFα and GM-CSF, and the cell viability of AML12 was measured by MTT method.

Rhein (30 mg/kg, ig) attenuates acute pancreatitis via suppressing excessive inflammation. The effect of Rhein decreased with prolonged use, which was characterized by the increase/no change of amylase and pro-inflammatory factors. Meanwhile, prolonged use induced the increase of serum AST, LDH and liver TNFα, accompanied by the increased amount of liver macrophage. After the macrophages were cleared by CL, Rhein-induced liver injury of AP mice was gone. Rhein induces the activation of macrophages in vitro and increases the secretion of TNFα, which indirectly leads to hepatocyte injury.

Rhein in appropriate doses has a protective effect on the pancreas, but prolonged use reduces the efficacy and risks liver injury. TNFα may be a marker of rhein-induced injury. This study provided preliminary experimental support for the clinical rational drug use and toxicity monitoring of rhubarb or anthraquinones in clinical use.