Computational modeling of the hepatocytes reveals new insights into alterations in drug metabolism, oxidative stress response, and glutathione detoxification in acetaminophen-induced hepatotoxicity associated with MASLD

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is one of the most common liver diseases worldwide, originating from abnormal fat accumulation in the liver. Acetaminophen (APAP) is a common antipyretic, but its overdose is a leading cause of acute liver failure. Clinical studies suggest that APAP-induced hepatotoxicity can be more frequent and severe in obese patients with MASLD. To investigate this process, we have developed a new mathematical model that comprehensively incorporates lipid metabolism, APAP metabolism, and glutathione (GSH) detoxification. In MASLD patients, we found that CYP and GST activities have higher sensitivity to ROS production than UGT and SULT, which are highly effective in detoxifying APAP. We also highlighted that the upregulation of GPx poses an unanticipated risk during steatosis by inducing an increase in H₂O₂. This occurs due to a vicious circle in which increasing NAPQI adducts further elevate H₂O₂ levels. According to clinical reports, the toxicity of APAP varies depending on the progression of MASLD. We simulated that the pool of enzymatic alterations observed in steatotic patients exacerbates APAP-induced toxicity, which is thought to be due to a significant upregulation of CYP2E1. In contrast, the enzyme changes in MASH patients alleviate APAP-induced toxicity, likely due to decreased activity of CYPs and increased activity of UGT and GST. We believe that our strategy, which couples lipid and drug metabolism, offers valuable pharmacological insights for identifying enzymes that play a significant role in liver injury and for devising future therapeutic strategies in the context of MASLD.