Nonalcoholic fatty liver disease (NAFLd) is a fat metabolism disorder that occurs in liver cells. The development of NAFLd is considered to be associated with hepatic oxidative stress. The present study aimed to investigate the role of cytochrome P450 4A11 (cYP4A11) in the pathogenesis of NAFLd. The levels of plasma cYP4A11 and lipid peroxidation products levels exhibited a high correlation, and were increased significantly compared with those from normal subjects. Further in vitro studies demonstrated that the expression levels of cYP4A11 and the content of reactive oxygen species (ROS) were increased in free fatty acid (FFA)-stimulated HepG2 cells. Clofibrate, a CYP4A11 inducer, aggravated cell damage. Opposite results were observed for the cYP4A11 inhibitor HET0016, which attenuated apoptosis in FFA-treated cells. Furthermore, cYP4A11 gene overexpression and silencing were used to investigate the effects on inflammatory cytokine secretion. The data demonstrated that cYP4A11 promoted an increase in the mRNA expression of tumor necrosis factor α, interleukin (IL)-1β and IL-6 in response to FFA. In addition, western blot analysis highlighted that cYP4A11 caused an upregulation of phosphorylated p65 levels and therefore affected the NF-κB signaling pathway. The data demonstrated that cYP4A11 may metabolize fatty acids to promote the production of ROS and accelerate the progression of NAFLd.

Nonalcoholic fatty liver disease (NAFLD) is a chronic hepatic disease associated with excessive accumulation of lipids in hepatocytes. As the disease progresses, oxidative stress plays a pivotal role in the development of hepatic lipid peroxidation. Cytochrome P450 1A1 (CYP1A1), a subtype of the cytochrome P450 family, has been shown to be a vital modulator in production of reactive oxygen species. However, the exact role of CYP1A1 in NAFLD is still unclear. The aim of this study was to investigate the effects of CYP1A1 on lipid peroxidation in oleic acid (OA)-treated human hepatoma cells (HepG2). We found that the expression of CYP1A1 is elevated in OA-stimulated HepG2 cells. The results of siRNA transfection analysis indicated that CYP1A1-siRNA inhibited the lipid peroxidation in OA-treated HepG2 cells. Additionally, compared with siRNA-transfected and benzo[a]pyrene (BaP)-OA-induced HepG2 cells, overexpression of CYP1A1 by BaP further accelerated the lipid peroxidation in OA-treated HepG2 cells. These observations reveal a regulatory role of CYP1A1 in liver lipid peroxidation and imply CYP1A1 as a potential therapeutic target.

Teriflunomide (TEF, A771726) is the active metabolite of leflunomide (LEF), a disease-modifying antirheumatic drug. The main purpose of this study was to develop and evaluate water-in-oil (W/O) microemulsion formulation of TEF. The W/O microemulsion was optimized formula is the physical and chemical stability of lecithin, ethanol, isopropyl myristate (IPM) and water (20.65/20.78/41.52/17.05 w/w) by using the pseudo-ternary phase diagram and the average droplet size is about 40 nm. The permeability of TEF microemulsion is about 6 times higher than control group in vitro penetration test. The results of antiinflammatory effect showed that compared with the control group, the external TEF microemulsion group could significantly inhibit swelling of paw in rats, and no significant difference compared with oral LEF group. The results of hepatotoxicity test show that there were normal content of alanine aminotransferase (ALT)/aspartate aminotransferase (AST) and no obvious inflammatory infiltration of TEF microemulsion group compared with LEF group. The plasma concentration curve showed that compared with LEF group, the peak concentration of TEF microemulsion group was decreased, the half-life (t 1/2) was prolonged, and the relative bioavailability of TEF microemulsion was 75.35%. These results suggest that TEF W/O microemulsion can be used as a promising preparation to play an anti-inflammatory role while significantly reducing hepatotoxicity.