Co-Induction of CYP3A12 and 3A26 in Dog Liver Slices by Xenobiotics: Species Difference Between Human and Dog CYP3A Induction

Jun      Chen; Cindy      Tran; Li      Xiao; Jairam      Palamanda; Thomas      Klapmuts; Pramila      Kumari; Xinjie      Lin; Er-jia      Wang; Yi-Zhong      Gu; Mary      Humphries; Annette   S.   Uss; K.-C.      Cheng

Abstract

The induction of dog CYP3A12 and CYP3A26 mRNA levels was evaluated in liver slices after treatment with 22 xenobiotics. Eleven of the 22 xenobiotics increased 3A12 mRNA by more than four-fold, while nine did the same for 3A26 mRNA. A four-fold increase in the mRNA level was used as the cut-off for indication of induction based on the noise level of the real time-PCR. A good correlation was found between the mRNA levels for 3A12 and 3A26 after treatment with compounds, suggesting that these two CYPs may be co-induced. Induction of CYP3A4 in human hepatocytes was evaluated after treatment with the same 22 compounds. Thirteen out of the 22 compounds increased the 3A4 mRNA levels by more than four-fold. When the mRNA levels of 3A4 and 3A12 were compared after treatment with compounds, no correlation was found. The regulation of CYP3A expression has been demonstrated to be controlled by pregnane X receptor (PXR). Upon examination of the sequence homology and the three-dimensional structures of human PXR and a dog PXR model, only two different amino acids (met323/val and arg410/lys) were found in the ligand-binding domain. This finding suggests that these two amino acids may play a role in the binding specificity of ligands.

Keywords: CYP 3A induction, pregnane X receptor, species difference

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