Different Diets Cause Alterations in the Enteric Environment and Trigger Changes in the Expression of Hepatic Cytochrome P450 3A, a Drug-Metabolizing Enzyme

Abstract

Changes in the expression level and activity of cytochrome P450 (CYP) in the liver are caused by various factors and affect the pharmacokinetics of drugs. The purpose of this study was to determine whether the expression of CYP3A is affected by a high-fat diet. In addition, we examined whether the type of diet given to mice could produce changes in the expression level and activity of CYP3A. Mice were fed a purified diet containing 10 kcal% lard (control group) or 60 kcal% lard (HF group) or regular mouse chow containing 13 kcal% of fat (MF group) for 4 weeks. No significant differences were observed in the hepatic CYP3A protein expression level between the HF group and the control group. The CYP3A protein expression in the MF group was significantly higher than that observed in the control group. In the MF group, the area under the curve (AUC) of intraperitoneally administered triazolam was lower. Because lithocholic acid (LCA) is known to increase hepatic CYP3A expression, the levels of Clostridium sordellii and LCA in the feces were measured. In the MF group, the levels of Clostridium sordellii and LCA were higher. It has been demonstrated that a high-fat diet does not cause any changes in hepatic CYP3A expression. In addition, the different diets caused alterations in the enteric environment, which triggered changes in CYP3A expression. Therefore, it is necessary to carefully consider the type of feed while performing animal experiments to evaluate the pharmacokinetics of drugs.

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

“…Our laboratory previously reported that CYP, especially CYP3A, activity was induced more in mice fed a low protein diet (7% (w/w) casein) than in mice fed a control diet (20% (w/w) casein) [20][21][22]. A high-fat diet (P:F:C = 20:60:20) did not cause any changes in the hepatic expression of CYP3A, whereas regular chow (P:F:C = 26:13:61) increased CYP3A11 mRNA and CYP3A protein expression levels in the livers of mice more than the control diet (P:F:C = 20:10:70) [23]. Furthermore, although changes in dietary fat composition did not alter the induction of CYP2E1, hepatic CYP4A mRNA and protein expression levels were markedly increased in rats fed a saturated fat rich diet [24].…”

A Bioequivalence Study of Avanafil in Healthy Chinese Male Subjects Under Fasting and Fed Conditions: Results of a Randomized, Open‐Label, Single‐Dose, 2‐Sequence, 2‐Period Crossover Study

“…8 Otherwise, even though concomitant food intake may delay the absorption of avanafil, high-calorie diets do not significantly influence CYP3A4 activity. 16 The safety results revealed that all AEs were TEAEs in both the fasting and fed trials, with an incidence of 20.8% and 20.7%, respectively. The severity of AEs were both grade 1, and except for the unknown outcome of 2 subjects in the fed trial, all the remaining subjects were cured or had greatly improved symptoms without the need for further therapy.…”

“… 8 Otherwise, even though concomitant food intake may delay the absorption of avanafil, high‐calorie diets do not significantly influence CYP3A4 activity. 16 …”

Prebiotic effects of commercial apple juice in high-fat diet fed rat

“…The human gut is home to an abundant and diverse community of bacteria; each person carries approximately 100 trillion bacterial cells, representing more than 1,000 different species [9]. The abundance of intestinal bacteria changes depending on diet [15][16][17] and drug intake [18][19][20]. In recent years, intestinal bacteria have been reported to change dynamically during the onset of ulcerative colitis [21], obesity [22,23], and diabetes [24], and the importance of intestinal bacteria as a factor in the onset and exacerbation of these diseases has been highlighted.…”