The Major Cytochrome P450 Subtype Activities in Diet-Induced Non- Alcoholic Steatohepatitis Mouse Model

Abstract

Objective: Non-Alcoholic Steato Hepatitis (NASH) is now recognized as a global liver disease. Medication combined with diet and exercise regimen is used to treat NASH, because NASH is associated with metabolic syndrome, such as insulin resistance or dyslipidemia. However, it currently remains unclear whether NASH affects the metabolic power and activity in the liver especially for hypo-cholesterolemic drugs. To address this issue, we measured major Cytochrome P450 (CYP) subtype activities in mice with diet-induced NASH.Methods: C57BL/6J mice (male, 8 weeks of age) were fed a High-Fat and High-Cholesterol (HFHC) diet or normal chow diet (control) ad libitum for 12 weeks. Plasma lipid levels and hepatic lipid contents were then measured. The mRNA expression levels of the CYP subtypes and inflammatory cytokines in the liver were assessed using quantitative RT-PCR methods. Liver microsomal CYP activities were evaluated by luminogenic CYP assays.Results: Body weight was significantly lower and the liver weight was higher in HFHC-fed mice than in control mice. Plasma levels of AST, ALT, and ALP were higher in HFHC-fed mice. Oil red O staining and the evaluation of hepatic lipid contents revealed the accumulation of lipids in the liver of HFHC-fed mice. Furthermore, increased inflammatory cytokine (ex. IL-1β, IL-6, and TNF-α) mRNA expression in the liver and a pathological analysis confirmed the characteristics of NASH in HFHC-fed mice. CYP1A1, 1A2, and 3A activities were higher in HFHC-fed mice than in control, which were coincident with mRNA expression levels in the liver. However, CYP2C activity was significantly lower, even though CYP2C29 mRNA expression was higher in HFHC-fed mice than in control mice. Conclusion:These results indicated that major CYP subtypes activities in the liver were influenced in NASH mice model. It could be occurred in human, and physicians need to consider the administration of appropriate medication to patients with NASH.

<i>Coleus forskohlii</i> Extract Attenuated the Beneficial Effect of Diet-Treatment on NASH in Mouse Model

“…Previously, our group reported that mice fed a 0.5% CFE in control diet for 3 wk, which is the same condition in this experiment, showed markedly induced hepatic CYP2B, CYP2C, and CYP3A activities (28). In addition, we also reported that CYP1A1, 1A2, and 3A activities were higher in HFHC-diet induced NASH mice than in control, whereas CYP2C activity was significantly lower in HFHC-diet induced NASH mice compared to control mice (36). So, we evaluated whether CFE affect CYP activity during diet-treatment and/or exercise in NASH.…”

Colon Cancer Risk of a Westernized Diet Is Reduced in Mice by Feeding Cruciferous or Apiaceous Vegetables at a Lower Dose of Carcinogen but Not a Higher Dose

“…However, the TWD has a greater dietary fat concentration than the basal diet and contains cholesterol. Since mice fed a high fat high cholesterol diet were shown to have greater hepatic gene expression of CYP1A2 than mice fed a normal fat cholesterol free diet [ 55 ], the greater fat and cholesterol content of the TWD diet may be responsible for the increased CYP1A2 activity in mice fed the TWD, compared to the basal diet. The activity of UGT1A did not differ between the TWD and basal diets, suggesting that the TWD did not influence PhIP detoxification by glucuronidation.…”