Newly identified tree shrew cytochrome P450 2B6 (CYP2B6) and pig CYP2B6b are functional drug-metabolising enzymes

Abstract

1. Tree shrews have high phylogenetic affinity to humans and are used in various fields of biomedical research, especially hepatitis virus infection; however, cytochromes P450 (P450s or CYPs) have not been investigated in this species.

2. In this study, tree shrew CYP2B6 and pig CYP2B6b were newly identified and had amino acid sequences highly identical (80% and 78%, respectively) to human CYP2B6, containing sequence motifs characteristic of P450s.

3. Phylogenetic analysis revealed that novel tree shrew CYP2B6 was more closely related to known human CYP2B6 than dog, pig, or rat CYP2Bs are.

4. Among the tissue types analysed, tree shrew CYP2B6 mRNA was preferentially expressed in liver and lung, whereas pig CYP2B6b mRNA was preferentially expressed in jejunum and lung.

5. Tree shrew CYP2B6 and pig CYP2B6b proteins heterologously expressed in Escherichia coli metabolised human CYP2B6 substrates efavirenz, ethoxycoumarin, propofol, and testosterone, suggesting that these novel CYP2Bs are functional drug-metabolizing enzymes in liver and/or lung.

Keywords:

• Dog
• human
• minipig
• P450 2B6
• tupaia

Acknowledgments

The authors thank Yutaro Noda, Saho Morikuni, Asuka Oguchi, Koichiro Adachi, and Makiko Shimizu for their support of this work. The authors also greatly thank David Smallbones for copyediting a draft of this article.

Disclosure statement

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

Additional information

Funding

This work was supported partly by the Japan Society for the Promotion of Science Grant-in-Aid for Scientific Research 20K06434.