Effects of the hepatic mitochondrial ROS/TNF-α axis on bilirubin metabolism in aged rats and the regulatory mechanism of melatonin

OBJECTIVE: To analyze the effects of the hepatic mitochondrial reactive oxygen species (ROS)/tumor necrosis factor (TNF)-α axis on bilirubin metabolism in aged rats and the regulatory mechanism of melatonin. METHODS: 10 3-month-old SPF male SD rats were selected as the young group (intraperitoneal injection of normal saline), and 30 20-month-old rats were divided into an aged group (intraperitoneal injection of normal saline) and low- and high-dose melatonin groups (intraperitoneal injection of 5 and 10 mg/kg melatonin, respectively), with 10 rats in each group. Liver histopathology and hepatocyte mitochondrial morphology were observed in each group; hepatic mitochondrial permeability, mitochondrial membrane potential, serum bilirubin levels [total bilirubin (TBIL), direct bilirubin (DBIL), and indirect bilirubin (IBIL)], liver tissue malondialdehyde (MDA) content, superoxide dismutase (SOD) activity, and reactive oxygen species (ROS) and tumor necrosis factor (TNF)-α protein expression were measured. RESULTS: Compared with the aged group, the low- and high-dose melatonin groups showed decreased mitochondrial permeability, TBIL, DBIL, and IBIL levels, MDA content, and ROS and TNF-α protein expression, and increased mitochondrial membrane potential and SOD activity, with significant differences (P＜0.05). Improvements in the above indicators were significantly greatest in the high-dose melatonin group (P＜0.05). CONCLUSIONS: Activation of the mitochondrial ROS/TNF-α axis in the aged liver can lead to disordered bilirubin metabolism. Melatonin can improve hepatic bilirubin metabolism in aged rats by regulating this axis, with greater efficacy at the high dose.