ReviewThe marmoset cytochrome P450 superfamily: Sequence/phylogenetic analyses, genomic structure, and catalytic function
Graphical abstract
Introduction
Because of their close genetic and physiological similarities to humans, nonhuman primates are important species for evaluating the safety and therapeutic efficacy of candidates for drug development. The common marmoset (Callithrix jacchus), a New World monkey, is a potentially useful primate in efficacy/pharmacology, safety/toxicology, and drug metabolism and pharmacokinetic studies for preclinical testing. The common marmoset has various advantages, such as genetic closeness to humans, small size, fast maturation, high fertility, and ease of handling [1]. Marmosets have been favored for biomedical research in fields such as neurobiology [2], immunology [3], obesity [4], and aging [5]. The cynomolgus macaque (Macaca fascicularis), an Old World monkey, has been widely used as a preclinical model in drug metabolism and pharmacokinetic studies because of its availability and its long history of use as a laboratory animal species.
Cytochromes P450 (P450) constitute a superfamily of heme-thiolate enzymes that mediate the biotransformation and metabolism of endogenous steroid hormones, xenobiotics, and drugs. Currently known human P450 isoforms are encoded by 57 functional genes and 58 pseudogenes [6]. P450 enzymes in the P450 1A, 2B, 2C, 2D, 2E, and 3A subfamilies are major drug-metabolizing enzymes [7], whereas those in the P450 4 family are involved in the metabolism of endogenous [8] and exogenous compounds [9]. P450 enzymes can catalyze various types of enzymatic reactions, including hydroxylation, dealkylation, sulfoxidation, epoxidation, and N-oxidation [10]. Interspecies differences of P450-mediated drug metabolism have been identified in commonly used preclinical animal species, including mice, rats, dogs, pigs, and cynomolgus macaques [11]. Consequently, to select appropriate animal species for drug metabolism and pharmacokinetic studies, it is important to understand the orthologous relationships and functional characteristics of their P450 isoforms.
In 2013, the Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS) project was set up. Its aims were to accelerate the understanding of human brain disorders using marmosets and to facilitate the use of marmosets for drug development [12]. However, despite the importance of the marmoset as a preclinical nonhuman primate species, only limited numbers of P450 isoforms have been identified, including P450 1A2, 2B6, 2C8, 2D6, 2E1, 3A4, 3A5, and 3A90. We participated in the Brain/MINDS project to investigate the characteristics of drug metabolism and pharmacokinetics in marmosets. By using transcriptome data of marmoset tissues obtained by next-generation high-throughput RNA sequencing analysis [13] and by using marmoset genome data based on whole-genome shotgun sequencing and assembly [14], we identified and characterized a large number of marmoset P450 isoforms in the P450 1–51 families (see http://drnelson.uthsc.edu/CytochromeP450.html). Our understanding of P450-mediated drug metabolism has been accelerated by the comprehensive cDNA cloning and functional analyses of marmoset P450 isoforms carried out as part of the Brain/MINDS project. This mini-review compares the characteristics of the P450 1A, 2A, 2B, 2C, 2D, 2E, and 3A subfamilies in marmosets and humans.
Section snippets
Gene identification, cDNA cloning, and phylogenetic analysis of marmoset P450s
Marmoset P450 1–51 gene clusters were analyzed based on marmoset genome data in the UCSC Genome Browser (https://genome.ucsc.edu/index.html) (Fig. 1). The locations and directions of most marmoset P450 1–51 genes in gene clusters are well conserved with those of human P450 genes. However, the gene arrangements of the P450 2ABFGST, 2C, 2D, 3A, 4ABXZ, and 4F clusters are slightly different between humans and marmosets. In the P450 1 family, gene arrangements in the P450 1A, 1B, and 1D clusters
Conclusions and future perspectives
This mini-review provides a comprehensive description of the gene organization, sequence identity, phylogeny, tissue distribution, induction, and substrate specificity of marmoset P450 1–4 family members and makes comparisons with human P450 isoforms. Several remarkable characteristics of marmoset P450 1–4 family members are revealed, including the partial differences of genomic organization in the P450 2ABFGST, 2C, 2D, 3A, 4ABXZ, and 4F clusters; the similarities of P450 1A1/1A2 and 3A4
CRediT authorship contribution statement
Shotaro Uehara: Formal analysis, Investigation. Yasuhiro Uno: Investigation. Hiroshi Yamazaki: Writing - original draft, Writing - review & editing.
Acknowledgments
We thank Drs. Erika Sasaki, Takashi Inoue, Norie Murayama, and Makiko Shimizu for their support with the experiments. The authors also greatly thank David Smallbones for copyediting a draft of this article. 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.
Declaration of interest
The authors report no declarations of interest.
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2022, Advances in PharmacologyCitation Excerpt :CYP2D genes are arranged in the human genome differently than in the macaque and marmoset genomes, and CYP2D8, a pseudogene in humans, encodes a functional enzyme in macaques and marmosets (Uehara, Uno, & Yamazaki, 2020; Uno, Iwasaki, et al., 2011). For CYP3A genes, the number and arrangements of genes in the genome are well-conserved between humans and macaques, but not between humans and marmosets (Uehara, Uno, & Yamazaki, 2020; Uno, Iwasaki, et al., 2011). Marmoset CYP3A5 and CYP3A90, which are highly homologous to human CYP3A5, are functional enzymes, whereas the marmoset genome does not contain a CYP3A43 ortholog.
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These authors contributed equally.