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

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.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.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.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. 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. 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. 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. 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.

谷胱甘肽S-转移酶（GSTs）是一类参与药物代谢、抗氧化防御以及细胞信号传导的结合酶。本研究针对多株小鼠和大鼠品系（涵盖雌雄两性）的肝脏GST结合反应进行了探究，并直接与人类样本开展对比。采用通用型及同工型选择性底物进行检测后发现，所有小鼠品系的总胞质GST、GST-M、GST-T以及微粒体GST活性均显著高于人类；部分品系的GST-P活性同样显著高于人类。在所有小鼠品系中，总胞质GST、GST-M及GST-P活性均存在显著的雌雄性别差异；而部分品系的GST-T及微粒体GST活性也呈现出性别差异。所有大鼠品系的GST-M与GST-T活性均显著高于人类；仅部分品系的GST-P、总胞质GST以及微粒体GST活性显著高于人类。大鼠品系内的性别差异表现为：雄性个体的GST-M与GST-T活性显著高于雌性；部分品系的总胞质GST及微粒体GST活性存在性别差异，而GST-P活性则无明显性别差异。人类与啮齿类动物在谷胱甘肽结合反应层面存在显著差异，其中亦包含性别相关差异。这一结果提示，在以GSTs为主要代谢通路的临床前研究中，需谨慎选择实验动物。谷胱甘肽S-转移酶（GSTs）是一类参与药物代谢、抗氧化防御以及细胞信号传导的结合酶。本研究针对多株小鼠和大鼠品系（涵盖雌雄两性）的肝脏GST结合反应进行了探究，并直接与人类样本开展对比。采用通用型及同工型选择性底物进行检测后发现，所有小鼠品系的总胞质GST、GST-M、GST-T以及微粒体GST活性均显著高于人类；部分品系的GST-P活性同样显著高于人类。在所有小鼠品系中，总胞质GST、GST-M及GST-P活性均存在显著的雌雄性别差异；而部分品系的GST-T及微粒体GST活性也呈现出性别差异。所有大鼠品系的GST-M与GST-T活性均显著高于人类；仅部分品系的GST-P、总胞质GST以及微粒体GST活性显著高于人类。大鼠品系内的性别差异表现为：雄性个体的GST-M与GST-T活性显著高于雌性；部分品系的总胞质GST及微粒体GST活性存在性别差异，而GST-P活性则无明显性别差异。人类与啮齿类动物在谷胱甘肽结合反应层面存在显著差异，其中亦包含性别相关差异。这一结果提示，在以GSTs为主要代谢通路的临床前研究中，需谨慎选择实验动物。