Acetaminophen-Induced Hepatotoxicity in Obesity and Nonalcoholic Fatty Liver Disease: A Critical Review

Abstract

The epidemic of obesity, type 2 diabetes and nonalcoholic liver disease (NAFLD) favors drug consumption, which augments the risk of adverse events including liver injury. For more than 30 years, a series of experimental and clinical investigations reported or suggested that the common pain reliever acetaminophen (APAP) could be more hepatotoxic in obesity and related metabolic diseases, at least after an overdose. Nonetheless, several investigations did not reproduce these data. This discrepancy might come from the extent of obesity and steatosis, accumulation of specific lipid species, mitochondrial dysfunction and diabetes-related parameters such as ketonemia and hyperglycemia. Among these factors, some of them seem pivotal for the induction of cytochrome P450 2E1 (CYP2E1), which favors the conversion of APAP to the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI). In contrast, other factors might explain why obesity and NAFLD are not always associated with more frequent or more severe APAP-induced acute hepatotoxicity, such as increased volume of distribution in the body, higher hepatic glucuronidation and reduced CYP3A4 activity. Accordingly, the occurrence and outcome of APAP-induced liver injury in an obese individual with NAFLD would depend on a delicate balance between metabolic factors that augment the generation of NAPQI and others that can mitigate hepatotoxicity.

Keywords: acetaminophen; cytochrome P450 2E1; diabetes; drug-induced liver injury; fatty acids; mitochondria; nonalcoholic fatty liver disease; nonalcoholic steatohepatitis; obesity; steatosis.

Figure 1.

Biotransformation and toxicity of APAP in normal liver. (A). For therapeutic dose, APAP is mainly detoxified through sulfation and glucuronidation, while a small proportion is metabolized to N-acetyl-p-benzoquinone imine (NAPQI) via the cytochrome P450 2E1 (CYP2E1) and to a lesser extent CYP3A4 and CYP1A2. In normal liver, the low amounts of NAPQI are efficiently detoxified by glutathione (GSH), a major antioxidant molecule present in different cellular compartments including mitochondria. (B). After APAP overdoses, the sulfation and glucuronidation pathways are overwhelmed and more APAP undergoes CYP-dependent oxidation to NAPQI. However, GSH concentrations in hepatocytes are not sufficient to allow the efficient detoxification of NAPQI, which then induces major mitochondrial dysfunction, oxidative stress and acute liver injury. More information is provided in the text.

Figure 2.

Hepatotoxicity of APAP in obesity and NAFLD. (A). Different factors in obesity and NAFLD could favor liver injury induced by APAP overdose, for instance by increasing cytochrome P450 2E1 (CYP2E1) activity, reducing basal concentrations of glutathione (GSH) and promoting preexisting mitochondrial dysfunction. In addition, the accumulation of cholesterol could sensitize the liver to APAP-induced hepatotoxicity by favoring mitochondrial GSH depletion. Lobular inflammation might also favor APAP hepatotoxicity via several cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and IL-6. (B). On the contrary, some factors in obesity and NAFLD could mitigate APAP-induced liver injury, for instance by increasing APAP glucuronidation and reducing CYP3A4 and CYP1A2 activity. Moreover, CYP2E1 induction could be absent or lost in some metabolic and pathological conditions. The absence of preexisting mitochondrial dysfunction in some patients might also mitigate APAP-induced hepatotoxicity. Consequently, obese people with one or several of these mitigating factors might not have a higher risk of severe APAP-induced liver injury. More information is provided in the text.