关键词: 姜黄素, 化学性与药物性肝损伤, 肝疾病, 酒精性, 细胞色素P-450 CYP3A, 孤儿核受体, 孕烷X受体, 组 成型雄甾烷受体

Abstract: Objective To investigate the effects of curcumin on cytochrome P450 3A (CYP3A) in rats with alcoholic
liver injury (ALD) and its mechanism. Methods Sixty ALD rats with successful modeling were randomly divided into the
model group, the curcumin low, medium and high dose groups (gavage 40, 80 and 160 mg/kg curcumin respectively) and the
positive control group (200 mg/kg ademetionine intraperitoneally), with 12 rats in each group. The control group (n=12) was
fed normally and given intragastric administration of equal volume of normal saline, for 6 consecutive weeks. The serum levels of
alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) were detected by automatic
biochemical analyzer. The morphological changes of liver were detected by hematoxylin-eosin (HE) staining. The mRNA levels
of pregnane X receptor (PXR), constitutive androstane receptor (CAR) and CYP3A25 were detected by quantitative real-time
PCR (qPCR). The protein levels of PXR and CAR were detected by Western blot assay. Rat primary hepatocytes were used to
culture with 0, 100, 200, 300, 400 and 500 mmol/L alcohol respectively, and the alcohol concentration was taken when the
cell proliferation inhibition rate was about 50% for the next experiment. 0, 0.5, 1.0, 2.0, 4.0, 8.0 and 16.0 μmol/L curcumin
cultured cells respectively, and the most suitable curcumin concentration was used for the next study. The experiments were
divided into the control group, the alcohol group, the curcumin group, the curcumin+siRNA-NC group and the curcumin+
siRNA-CYP3A25 group. The cell proliferation was detected by CCK-8. The level of CYP3A25 mRNA in cells was detected  by qPCR. The levels of PXR and CAR protein in cells were detected by Western blot assay. Results In the rat experiment:
compared with the control group, the serum levels of ALT, AST and ALP increased in the model group (P＜0.05). Compared
with the model group, the serum levels of ALT and ALP decreased in the curcumin low dose group, and the levels of PXR,
CAR mRNA and protein, CYP3A25 mRNA in liver tissue increased (P＜0.05). The serum levels of ALT, AST and ALP
decreased in the curcumin medium and high dose groups, while the levels of PXR, CAR mRNA and protein, CYP3A25
mRNA in liver tissue increased (P＜0.05). The indicators gradually recovered with the increase of dosage. In the cell
experiments: compared with the control group, the cell proliferation inhibition rate increased in the alcohol group (P＜0.05),
and the levels of PXR and CAR protein in cells decreased (P＜0.05). Compared with the alcohol group, the proliferation
inhibition rate decreased in the curcumin group (P＜0.05), the levels of CYP3A25 mRNA, PXR and CAR protein in cells
increased (P＜0.05). Compared with the curcumin group, the proliferation inhibition rate increased in the curcumin+siRNA
CYP3A25 group (P＜0.05), and the levels of CYP3A25 mRNA, PXR and CAR protein in cells decreased (P＜0.05).
Conclusion Curcumin can increase the level of CYP3A25 to promote drug metabolism and alleviate ALD. This process
may be related to the increase expression of PXR and CAR.

Key words: curcumin, chemical and drug induced liver injury, liver diseases, alcoholic, cytochrome P-450 CYP3, orphan nuclear receptors, pregnane X receptor, constitutive androstane receptor