The marmoset cytochrome P450 superfamily: Sequence/phylogenetic analyses, genomic structure, and catalytic function

Abstract

The common marmoset (Callithrix jacchus) is a New World monkey that has attracted much attention as a potentially useful primate model for preclinical testing. A total of 36 marmoset cytochrome P450 (P450) isoforms in the P450 1–51 subfamilies have been identified and characterized by the application of genome analysis and molecular functional characterization. In this mini-review, we provide an overview of the genomic structures, sequence identities, and substrate selectivities of marmoset P450s compared with those of human P450s. Based on the sequence identity, phylogeny, and genomic organization of marmoset P450s, orthologous relationships were established between human and marmoset P450s. Twenty-four members of the marmoset P450 1A, 2A, 2B, 2C, 2D, 2E, 3A, 4A, and 4F subfamilies shared high degrees of homology in terms of cDNA (>89%) and amino acid sequences (>85%) with the corresponding human P450s; P450 2C76 was among the exceptions. Phylogenetic analysis using amino acid sequences revealed that marmoset P450s in the P450 1–51 families were located in the same clades as their human and macaque P450 homologs. This finding underlines the evolutionary closeness of marmoset P450s to their human and macaque homologs. Most marmoset P450 1–4 enzymes catalyzed the typical drug-metabolizing reactions of the corresponding human P450 homologs, except for some differences of P450 2A6 and 2B6. Consequently, it appears that the substrate specificities of enzymes in the P450 1–4 families are generally similar in marmosets and humans. The information presented here supports a better understanding of the functional characteristics of marmoset P450s and their similarities and differences with human P450s. It is hoped that this mini-review will facilitate the successful use of marmosets as primate models in drug metabolism and pharmacokinetic studies.