Cross-species analysis of hepatic cytochrome P450 and transport protein expression

Abstract

Most drugs and xenobiotics are metabolized in the liver. Amongst others, different cytochrome P450 (CYP) enzymes catalyze the metabolic conversion of foreign compounds, and various transport proteins are engaged in the excretion of metabolites from the hepatocytes. Inter-species and inter-individual differences in the hepatic levels and activities of drug-metabolizing enzymes and transporters result from genetic as well as from environmental factors, and play a decisive role in determining the pharmacokinetic properties of a compound in a given test system. To allow for a meaningful comparison of results from metabolism studies, it is, therefore, of utmost importance to know about the specific metabolic properties of the test systems, especially about the levels of metabolic enzymes such as the CYPs. Using a targeted proteomics approach, we, therefore, compared the hepatic levels of important CYP enzymes and transporters in different experimental systems in vivo and in vitro, namely Wistar rats, C57/Bl6 mice, mice humanized for the two xeno-sensing receptors PXR (pregnane-X-receptor) and CAR (constitutive androstane receptor), mice with human hepatocyte-repopulated livers, human HepaRG hepatocarcinoma cells, primary human hepatocytes, and human liver biopsies. In addition, the effects of xenobiotic inducers of drug metabolism on CYP enzymes and transporters were analyzed in selected systems. This study for the first time presents a comprehensive overview of similarities and differences in important drug metabolism-related proteins among the different experimental models.

Gut microbiome affects the metabolism of metronidazole in mice through regulation of hepatic cytochromes P450 expression

“…For CYP2C, two substrates (diclofenac and diazepam) were used to cover the activities of characteristic for the most of the CYP2C forms involved. For the CYP2C38 activity, since it is similar to human CYP2C9 form [ 22 ], diclofenac was used as a substrate. The activity of CYP2C29 was determined by using diazepam as a substrate (murine CYP2C29 is homologous with human CYP2C19) [ 23 ].…”

Effects of Short- and Long-Term Soy Protein Feeding on Hepatic Cytochrome P450 Expression in Obese Nonalcoholic Fatty Liver Disease Rat Model

“…Studies have shown a dysregulation in CYP proteins during the progression of NAFLD ( 40 ). CYP protein families are found in high concentrations in the liver and are notably responsible for drug and exogenous substrate metabolism, detoxification of environmental chemicals, bioactivation of carcinogens, and the biosynthesis of endogenous substrates ( 41 , 42 ). In addition, they play significant roles in metabolizing noncellular materials, cholesterol, vitamin D, arachidonic and retinoic acids, eicosanoids, and the biosynthesis of bile acids and steroids ( 43 ).…”

Effect of Nigella sativa oil on pharmacokinetics and pharmacodynamics of gliclazide in rats

“…The effect of diabetes on the activity of CYP enzymes, particularly CYP3A, has been well established in human (Dostalek et al., 2012; Gravel et al., 2019) and animal models (Patoine et al., 2014). Nevertheless, hepatic expression of CYP2C11, the rat ortholog of human CYP2C9 (responsible for gliclazide metabolism) (Hammer et al., 2021; Pan et al., 2016) were similar between healthy Wistar and Goto‐Kakizaki rats, the latter of which represent a nonobese hereditary model for type 2 diabetes mellitus (Oh et al., 2012). This suggested a similar extent of hepatic CL of gliclazide irrespective of diabetic status.…”