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CYP2D44 polymorphisms in cynomolgus and rhesus macaques
Yasuhiro Uno1, Shotaro Uehara, Sakae Kohara
1Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd., 16-1 Minami Akasaka, Kainan, Wakayama, 642-0017, Japan, uno-yasuhiro@snbl.co.jp.
Molecular Biology Reports
|February 16, 2015
Summary
Genetic polymorphisms in macaque CYP2D44, a drug-metabolizing enzyme, were investigated. Several variants, including null alleles, were identified, potentially explaining metabolic variability in these important animal models.
Area of Science:
- Pharmacogenomics
- Drug Metabolism
- Primate Models
Background:
- Macaques (cynomolgus and rhesus) are crucial for drug metabolism research.
- CYP2D44 in macaques metabolizes common human CYP2D substrates.
- Human CYP2D6, homologous to CYP2D44, exhibits significant genetic polymorphism and metabolic variability.
Purpose of the Study:
- To investigate genetic polymorphisms in macaque CYP2D44.
- To identify variants affecting CYP2D44 enzyme activity.
- To explore the impact of these polymorphisms on drug metabolism variability in macaques.
Main Methods:
- Screening of CYP2D44 in 78 cynomolgus and 40 rhesus macaques.
- Identification and characterization of genetic variants using sequencing.
- Site-directed mutagenesis and metabolic assays to assess enzyme activity.
- Analysis of specific variants, including non-synonymous, nonsense, frameshift, and gene conversion mutations.
Main Results:
- Discovered 67 CYP2D44 variants, including 64 non-synonymous, 1 nonsense, and 2 frameshift mutations, plus 1 gene conversion.
- Identified 11 non-synonymous variants within substrate recognition sites.
- Demonstrated reduced bufuralol 1'-hydroxylation activity for variants S175N, V185L, A235G, R242G, R245K, and N337D.
- Found two null alleles (c.128T>del and c.664G>T) exclusively in Indonesian cynomolgus macaques.
Conclusions:
- Genetic polymorphisms in CYP2D44 are prevalent in macaques.
- Identified variants, particularly those in substrate recognition sites and null alleles, likely contribute to inter-individual variability in CYP2D44-dependent drug metabolism.
- These findings highlight the importance of considering macaque CYP2D44 genetic diversity in drug development studies.
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