Increased resistance to acetaminophen hepatotoxicity in mice lacking glutathione S-transferase Pi

Overdose of acetaminophen, a widely used analgesic drug, can result in seve re hepatotoxicity and is often fatal. This toxic reaction is associated wit h metabolic activation by the P450 system to form a quinoneimine metabolite . N-acetyl-p-benzoquinoneimine (NAPQI), which covalently binds to proteins and other macromolecules to cause cellular damage. At low doses, NAPQI is e fficiently detoxified, principally by conjugation with glutathione, a react ion catalyzed in part by the glutathione S-transferases (GST), such as CST Pi. To assess the role of GST in acetaminophen hepatotoxicity, we examined acetaminophen metabolism and liver damage in mice nulled for GstP (GstP1/P2 ((-/-))). Contrary to our expectations, instead of being more sensitive, Gs tP null mice were highly resistant to the hepatotoxic effects of this compo und. No significant differences between wild-type (GstP1/P2((+/+))) mice an d GstP1/ P2((-/-)) nulls in either the rate or route of metabolism, particu larly to glutathione conjugates, or in the levels of covalent binding of ac etaminophen-reactive metabolites to cellular protein were observed. However , although a similar rapid depletion of hepatic reduced glutathione (GSH) w as found in both GstP1/P2((+/+)) and GstP1/P2((-/-)) mice, GSH levels only recovered in the GstP1/P2((-/-)) mice. These data demonstrate that GstP doe s not contribute in vivo to the formation of glutathione conjugates of acet aminophen but plays a novel and unexpected role in the toxicity of this com pound. This study identifies new ways in which GST can modulate cellular se nsitivity to toxic effects and suggests that the level of CST Pi may be an important and contributing factor in the sensitivity of patients with aceta minophen-induced hepatotoxicity.