Temporal Evaluation of CYP mRNA in Mice Administered with Prototypical P450 Inducers: Comparison with Conventional Protein/Enzyme Methods

Abstract

Assessment of cytochrome P450 (CYP) induction at the mRNA level in preclinical rodent studies has gained interest in recent years, but there are still concerns regarding correlations between the mRNA and the enzyme activity levels, especially in mice. The purpose of the present study was to systematically evaluate patterns of temporal changes of CYPs 1a1, 1a2, 2b10, 3a11, and 4a10 at mRNA, protein, and activity levels in order to determine to what extent mRNA levels could be used either qualitatively or quantitatively for the assessment of CYP enzyme induction. In this study, livers from male CD-1 mice treated daily with β-naphthoflavone, phenobarbital, dexamethasone, clofibrate, and control vehicles were collected for RNA and microsomal analysis after 0.5, 1, 2, 4, and 8 days of daily dose. The results revealed a good correlation among mRNA, protein, and enzyme activity levels, with the best correlation at the time points between Days 2 and 8, suggesting that the appropriate time to monitor CYP mRNA may be beyond Day 2 of chemical treatments. Based on these results, we concluded that the mRNA approach is a useful tool to monitor CYP induction in mice, particularly when treatment duration is beyond 2 days.

Keywords:

• CYP induction
• Liver
• Chemicals
• Mice

ACKNOWLEDGMENT

The authors thank Dr. Philip Sherratt, Ph.D., for his critical reading of the manuscript and Mr. Genry Zairov for his contribution of RNA extraction.

Declaration of interest: The authors report no conflict of interest. The authors alone are responsible for the content and writing of this paper.