Comparison of mouse and human cytochrome P450 mediated-drug metabolising activities in hepatic and extrahepatic microsomes

Abstract

1. Despite the importance of mice as a preclinical species in drug testing, their hepatic and extrahepatic drug-metabolising characteristics are poorly understood. Here, we compared the P450-dependent drug oxidation activity in tissue microsomes and distribution patterns of P450 protein/mRNA between humans and mice.

2. The activities of midazolam 1′-/4-hydroxylation in the liver and intestine and chlorzoxazone 6-hydroxylation in the liver were similar in humans and mice. The activities of coumarin 7-hydroxylation, flurbiprofen 4′-hydroxylation, and S-mephenytoin 4′-hydroxylation in the liver were higher in humans than in mice. The activities of 7-ethoxyresorufin O-deethylation in the liver, 7-pentoxyresorufin O-depentylation in the lung/liver/intestine, bufuralol 1′-hydroxylation in the liver/intestine, propafenone 4′-hydroxylation in liver/intestine, and diazepam N-demethylation in the liver/intestine were higher in mice than in humans.

3. CYP1A2/2E1 mRNAs were mainly expressed in the livers of humans and mice. Cyp2b9/2b10 mRNAs were abundant in the mouse lung/liver/intestine, but CYP2B6 was mainly expressed in the human liver. CYP2C/2D/3A mRNAs were expressed in the liver and intestine, with the respective proteins detected in tissue microsomes of both humans and mice.

4. These information on P450-dependent drug-metabolising characteristics in hepatic and extrahepatic tissues is useful to understand the similarities and differences between humans and mice in drug metabolism.

Keywords:

• Cytochrome P450
• drug oxidation
• hepatic and extrahepatic tissues
• species differences
• 7-pentoxyresorufin
• bufuralol
• propafenone
• diazepam

Acknowledgements

We sincerely thank Dr. Mamoru Ito, Dr. Hidetaka Kamimura, Mr. Yasuhiko Ando, Mr. Hiroaki Kato, and Mr. Takaya Honma for their support. We would like to thank Editage (www.editage.com) for English language editing.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This research was partially supported by the Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)) from AMED under grant [number 21am0101121j0005]. SU and HY were supported in part by the Japan Society for the Promotion of Science Grant-in-Aid for Scientific Research [20K06463 and 20K07164, respectively].