Marmoset cytochrome P450 2B6, a propofol hydroxylase expressed in liver

Abstract

1. The common marmoset (Callithrix jacchus) is a useful experimental animal to evaluate the pharmacokinetics of drug candidates. Cytochrome P450 (P450) 2B enzyme in marmoset livers has been identified; however, only limited information on the enzymatic properties and distribution has been available.

2. Marmoset P450 2B6 amino acids showed high sequence identities (>86%) with those of primates including humans and cynomolgus monkeys. Phylogenetic analysis using amino acid sequences indicated that marmoset P450 2B6 was closer to human and cynomolgus monkey P450 2B6 than to P450 2B orthologs of other species, including pigs, dogs, rabbits and rodents.

3. Quantitative polymerase chain reaction analysis using specific primers showed P450 2B6 mRNA predominantly expressed in livers among the five marmoset tissues, similar to those of humans and cynomolgus monkeys.

4. Marmoset P450 2B6 heterologously expressed in Escherichia coli membranes oxidized 7-ethoxycoumarin, pentoxyresorufin, propofol and testosterone, at roughly similar rates to those of humans and/or cynomolgus monkeys. A high capacity of marmoset P450 2B6 with propofol 4-hydroxylation (at low ionic strength conditions) with a low K_m value was relatively comparable to that for marmoset livers.

5. These results collectively indicated a high propofol 4-hydroxylation activity of P450 2B6 expressed in marmoset livers.

Keywords:

• Common marmoset
• CYP2B6
• drug oxidation

Acknowledgments

The authors thank Drs. Makiko Shimizu, Yusuke Kamiya and Norie Murayama for their technical help and Mr. Lance Bell for his advice on English writing.

Disclosure statement

This work resulted from the “Construction of System for Spread of Primate Model Animals” initiative under the Strategic Research Program for Brain Sciences of the Japan Agency for Medical Research and Development. The authors alone are responsible for the content and for writing the article and report no conflicts of interest.

Additional information

Funding

Shotaro Uehara was supported partly by the Japan Society for the Promotion of Science Grant-in-Aid for Young Scientists B [17K15520].