Common marmosets (Callithrix jacchus), small New World primates, are increasingly attracting attention as potentially useful animal models for drug development. However, characterization of cytochrome P450 (P450) 3A enzymes involved in the metabolism of a wide variety of drugs has remained in marmosets. In this study, sequence homology, tissue distribution, and enzymatic property of marmoset P450 3A4 orthologue, 3A5 orthologue, and 3A90 were investigated. Marmoset P450 3A forms exhibited high amino acid sequence identities (88-90%) to the human and cynomolgus monkey P450 3A orthologues and evolutionary closeness to human and cynomolgus monkey P450 3A orthologues, compared with other P450 3A enzymes. Among the five marmoset tissues examined, P450 3A4 orthologue mRNA was abundant in livers and small intestines where P450 3A4 orthologue proteins were immunologically detected. Three marmoset P450 3A proteins heterologously expressed in Escherichia coli membranes catalyzed midazolam 1'- and 4-hydroxylation, alprazolam 4-hydroxylation, nifedipine oxidation, and testosterone 6β-hydroxylation, like cynomolgus monkey and human P450 3A enzymes. Among the marmoset P450 3A enzymes, P450 3A4 orthologue effectively catalyzed midazolam 1'-hydroxylation, comparable to microsomes from marmoset livers and small intestines. Correlation analyses with 23 individual marmoset liver microsomes suggested contributions of P450 3A enzymes to both 1'-hydroxylation of midazolam (human P450 3A probe) and bufuralol (human P450 2D6 probe), like cynomolgus monkey P450 3A enzymes. These results indicated that marmoset P450 3A forms had the functional characteristics roughly similar to cynomolgus monkeys and humans in term of tissue expression patterns and catalytic activities, suggesting marmosets as suitable animal models for P450 3A-dependent drug metabolism.
- The American Society for Pharmacology and Experimental Therapeutics