Utilization ofglutathione S-transferase Mu 1- andTheta 1-null mice as animal models for absorption, distribution, metabolism, excretion and toxicity studies

Abstract

Glutathione S-transferases (GSTs) are Phase II drug-metabolizing enzymes that catalyze the conjugation of electrophilic compounds to glutathione. This reaction generally detoxifies reactive metabolites of xenobiotics, such as drugs and environmental chemicals, and therefore, GSTs are considered toxicologically important enzymes. Human GST genes display genetic polymorphisms, and the impact of null genotypes of GST Mu 1 (GSTM1) and GST Theta 1 (GSTT1) have been extensively studied. Recently, corresponding Gstm1- and Gstt1-null mice have been developed. This review covers GSTM1- and GSTT1-null genotypes in humans and utilization of Gstm1- and Gstt1-null mice as animal models for absorption, distribution, metabolism, excretion and toxicity (ADMET) studies. Furthermore, the possibility of Gstm1- and Gstt1-null mice as models of humans with GSTM1- and GSTT1-null genotypes is discussed. The experimental approach to assess the impact of GSTM1- and GSTT1- null genotypes on ADMET is very limited so far. Gstm1- and Gstt1-null mice have potential as human models, since null genotypes of GSTM1/Gstm1 and GSTT1/Gstt1 decreased hepatic GST activities toward p-nitrobenzyl chloride and dichloromethane, respectively, in both humans and mice. This suggests functional similarity of GSTM1 and GSTT1 toward some substrates between humans and mice.