High-Fat Diet Feeding Alters Expression of Hepatic Drug-Metabolizing Enzymes in Mice

Abstract

Medical conditions accompanying obesity often require drug therapy, but whether and how obesity alters the expression of drug-metabolizing enzymes and thus drug pharmacokinetics is poorly defined. Previous studies have shown that high-fat diet (HFD) feeding and subsequent obesity in mice lead to altered expression of transcriptional regulators for cytochrome P450 CYP2D6, including hepatocyte nuclear factor 4 (HNF4, a transcriptional activator of CYP2D6) and small heterodimer partner (SHP, a transcriptional repressor of CYP2D6). The objective of this study was to examine whether diet-induced obesity alters CYP2D6 expression by modulating HNF4 and SHP expression. Male CYP2D6-humanized transgenic (Tg-CYP2D6) mice were fed with HFD or matching control diet for 18 weeks. Hepatic mRNA expression of CYP2D6 decreased to a small extent in the HFD group (by 31%), but the differences in CYP2D6 protein and activity levels in hepatic S9 fractions were found insignificant between the groups. Although hepatic SHP expression did not differ between the groups, HNF4 mRNA and protein levels decreased by ∼30% in the HFD group. Among major mouse endogenous cytochrome P450 genes, Cyp1a2 and Cyp2c37 showed significant decreases in the HFD group, whereas Cyp2e1 expression did not differ between groups. Cyp2b10 and Cyp3a11 expression was higher in the HFD group, with corresponding 2.9-fold increases in hepatic CYP3A activities in HFD-fed mice. Together, these results suggest that obesity has minimal effects on CYP2D6-mediated drug metabolism, although it modulates the expression of mouse endogenous P450s in a gene-specific manner.

Chronic exposure to a pollutant mixture at low doses led to tissue-specific metabolic alterations in male mice fed standard and high-fat high-sucrose diet

“…6B-C). Results in liver are consistent with previous reports (Fromenty, 2013) although discrepancies still exist regarding the regulation of Cyp3a11 expression in the liver of high-fat fed mice (Ning and Jeong, 2017). Intriguingly, expression levels of Cyp2b10, a CAR target gene (Aleksunes and Klaassen, 2012), was significantly down-regulated in jejunum and up-regulated in liver from HFHS-fed mice.…”

High fat diet significantly changed the global gene expression profile involved in hepatic drug metabolism and pharmacokinetic system in mice

“…Although data showed so many DMPK members regulated by high fat diet, there are still some unsolved problems. For example, a research regarding high fat diet and drug metabolizing enzymes revealed that high fat diet regulates endogenous CYPs in a gene-specific manner [10]. Until now, hundreds of CYP isozymes have been identified, but the effect of High fat diet effect on CYPs has not been fully understood.…”

Switching to a Healthy Diet Prevents the Detrimental Effects of Western Diet in a Colitis-Associated Colorectal Cancer Model

“…The WD increased significantly the expression of the hepatic Cyp3a11, the murine homolog of human CYP3A4, one of the key enzymes involved in drug metabolism [75] and in bile acid detoxification [76,77]. A recent study also showed that diets rich in saturated fat increase murine Cyp3a11 levels [78,79]. The diet switch was able to prevent the increase of Cyp3a11 an important observation for the treatment of IBD, because many drugs applied in IBD are metabolized by CYP3A4 [80].…”