Comparisons between human and rodent hepatic glutathione S-Transferase activities reveal sex and species differences

Abstract

1. Glutathione S-transferases (GSTs) are conjugating enzymes involved in drug metabolism, antioxidant defence, and cell signalling. Herein, we investigated hepatic GST conjugation in several mouse and rat strains, including both sexes, with a direct comparison to humans.

2. Using general and isoform-selective substrates, all mouse strains had significantly greater activities than humans for total cytosolic GST, GST-M, GST-T, and microsomal GST activities. Some strains had significantly greater GST-P activities compared to humans. Sex differences between males and females were evident in all strains for total cytosolic GST, GST-M, and GST-P, and sex differences in GST-T and microsomal GST activities within strains were noted.

3. All rats had significantly greater activities than humans for GST-M and GST-T; only some strains were significantly greater than humans for GST-P, total cytosolic GST, and microsomal GST. Sex differences within strains showed significantly greater GST-M and GST-T activities in males compared to females. Select strains showed sex differences for total cytosolic and microsomal GST activities; there were no sex differences in GST-P activities.

4. Significant differences in glutathione conjugation between humans and rodents exist, including sex differences. This highlights the need for careful animal selection in pre-clinical studies where GSTs are the primary metabolic pathway.

Keywords:

• Animal species conjugation drug metabolism glutathione S-transferases in-vitro-in vivo extrapolation risk prediction toxicology

Author contributions

Designed the study ACC; Carried out experiments, MJD, DS, ADS; Analysed data MJD, DS; data interpretation MJD, ADS, RSJ, MWHC, ACC; wrote or edited the manuscript MJD, DS, RSJ, ADS, MWHC, ACC. No Genentech products are researched or discussed in this manuscript.

Ethics approval

This study was reviewed and approved by the UBC Animal Care and Use Committee approval #A19-0227. Human tissues used as controls were from the Hawaii Comprehensive Biorepository and approved by The University of British Columbia’s Clinical Review Ethics Board approval (H14-00092). Biosafety approval was gained from UBC’s Biosafety Committee (B18-0009).

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The data are available upon request to the corresponding author.

Additional information

Funding

MJD is supported by an Alexander Graham Bell Canada Graduate Scholarship-Masters (CGS-M) from the National Science and Engineering Council of Canada (NSERC), and the Frank S. Abbott Graduate Fellowship in Pharmaceutical Sciences. ACC holds research grants from the NSERC Discovery Grants Program (17-3808), and a Genentech Research Grant that supported this work.