<i>In vivo</i> inhibition of CYP2E1 fails to reduce pulegone-induced liver injury in mice

Pulegone, an active component of the Chinese herb <i>Mentha haplocalyx</i> Briq., is primarily found in <i>Mentha arvensis</i> oil. It exerts toxic effects on the liver, nervous system, and kidneys, and its excessive intake leads to various adverse reactions and potentially fatal outcomes. CYP2E1 is considered the major metabolic enzyme that produces toxic metabolites of pulegone, which in turn cause toxicity in hepatocytes.This study aimed to establish a method for treating pulegone-induced acute liver injury <i>via in vivo</i> inhibition of CYP2E1 in mice.Acute liver toxicity was observed in mice intraperitoneally injected with 200 mg/kg pulegone, manifested as elevated serum levels of alanine aminotransferase (ALT) and aspartate transaminase (AST), disorganisation of the hepatic lobular structure, degeneration of hepatocytes, karyopyknosis, apoptosis, and upregulation of inflammatory factors. Hepatic CYP2E1 expression was inhibited by the delivery of siRNA in lipid nanoparticles in mice.However, experimental results showed that si-<i>Cyp2e1</i> LNPs could not ameliorate acute liver injury induced by pulegone. Interestingly, bicyclol could attenuate that liver injury in mice, which may be related to the inhibition of hepatocyte apoptosis. Pulegone, an active component of the Chinese herb <i>Mentha haplocalyx</i> Briq., is primarily found in <i>Mentha arvensis</i> oil. It exerts toxic effects on the liver, nervous system, and kidneys, and its excessive intake leads to various adverse reactions and potentially fatal outcomes. CYP2E1 is considered the major metabolic enzyme that produces toxic metabolites of pulegone, which in turn cause toxicity in hepatocytes. This study aimed to establish a method for treating pulegone-induced acute liver injury <i>via in vivo</i> inhibition of CYP2E1 in mice. Acute liver toxicity was observed in mice intraperitoneally injected with 200 mg/kg pulegone, manifested as elevated serum levels of alanine aminotransferase (ALT) and aspartate transaminase (AST), disorganisation of the hepatic lobular structure, degeneration of hepatocytes, karyopyknosis, apoptosis, and upregulation of inflammatory factors. Hepatic CYP2E1 expression was inhibited by the delivery of siRNA in lipid nanoparticles in mice. However, experimental results showed that si-<i>Cyp2e1</i> LNPs could not ameliorate acute liver injury induced by pulegone. Interestingly, bicyclol could attenuate that liver injury in mice, which may be related to the inhibition of hepatocyte apoptosis.