Genotoxicity evaluation using primary hepatocytes isolated from rhesus macaque (Macaca mulatta)

Area of Science:

• Toxicology
• Hepatology
• Genetics

Background:

• Non-human primates (NHPs) share physiological and genetic similarities with humans, making them valuable research models.
• Primary hepatocytes are crucial for studying drug metabolism and toxicity.

Purpose of the Study:

• To establish a method for isolating primary hepatocytes from rhesus macaque livers.
• To evaluate the utility of primary macaque hepatocytes (PMHs) as a surrogate for primary human hepatocytes (PHHs) in genotoxicity testing.

Main Methods:

• In situ whole liver perfusion to isolate PMHs from rhesus macaques.
• Treatment of PMHs with known genotoxic and non-genotoxic compounds.
• DNA damage assessment using the CometChip assay.
• Quantification of comet data using benchmark dose (BMD) modeling.

Main Results:

• PMHs demonstrated comparable sensitivity and specificity to PHHs in detecting direct-acting and indirect-acting genotoxicants.
• BMD50 values revealed species-specific differences in DNA damage potency, particularly for direct-acting compounds.
• The study successfully established a practical method for isolating and utilizing PMHs.

Conclusions:

• PMHs serve as a reliable surrogate for PHHs in evaluating the genotoxic hazards of chemical substances.
• This method maximizes the utility of NHP tissues in toxicological research.
• The findings support the use of PMHs in preclinical and translational safety studies for humans.