Short-Term High-Fat Diet Alters Acetaminophen Metabolism in Healthy Individuals

Abstract

Background: Acetaminophen is metabolized through a nontoxic sulfation and glucuronidation pathway and toxic oxidation pathway (via CYP2E1 and CYP1A2). A short-term high-fat diet induces alterations in the steatotic liver and may alter hepatic drug enzyme activity. In the case of acetaminophen, these alterations may result in an increased risk of hepatotoxicity. Therefore, this study was conducted to assess the effect of a 3-day hypercaloric high-fat diet on the plasma levels of acetaminophen metabolites.Methods: Nine healthy subjects participated in this randomized, crossover intervention study. The subjects consumed a regular diet or a regular diet supplemented with 500 mL of cream (1700 kcal) for 3 days and then fasted overnight. After ingesting 1000-mg acetaminophen, the plasma concentration of acetaminophen (APAP) and its metabolites [acetaminophen glucuronide, acetaminophen sulfate, 3-cysteinyl-acetaminophen, and 3-(N-acetyl-Lcystein-S-yl)-acetaminophen, and 3-methoxy-acetaminophen] were measured. Results:The 3-day high-fat diet increased the extrapolated area under the concentration-time curve from 0 to infinity (area under the curve 0-inf ) of APAP-Cys by approximately 20% (P = 0.02) and that from 0 to 8 hours (area under the curve 0-8 ) of APAP-Cys-NAC by approximately 39% (P = 0.01). The 3-day high-fat diet did not alter the pharmacokinetic parameters of the parent compound acetaminophen and other metabolites.Conclusions: A short-term, hypercaloric, high-fat diet increases the plasma levels of the APAP metabolites formed by the oxidation pathway, which may increase the risk of hepatotoxicity.

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

“…Accumulation of some fatty acids such as palmitic acid (C16:0) and stearic acid (C18:0) might play a role [ 74 , 98 , 99 ]. In keeping with the role of some fatty acids or lipids, a recent interventional study in healthy individuals showed that a short-term regular diet supplemented with whipped cream induced hepatic steatosis and significantly enhanced CYP2E1 activity [ 100 ]. Other mechanisms might involve hyperleptinemia, hyperglucagonemia and insulin resistance [ 10 , 25 , 82 ].…”

Supplementation of a high-fat diet with pentadecylresorcinol increases the representation of Akkermansia muciniphila in the mouse small and large intestines and may protect against complications caused by imbalanced nutrition

“…Quick snacks and fast foods enriched with simple sugars, fats, and flavorings create the impression of satiety and food satisfaction. Although there is an assurance that only a prolonged high-fat/highcarbohydrate diet leading to obesity and other metabolic diseases can cause sustainable changes in host and gut microbiota metabolism, in recent years, additional evidence of the crucial influence of a short-term high-fat diet on the gut microbiota and host metabolism has appeared 17,[26][27][28] . It is known that diet-induced changes in the gut microbiome occur rapidly (within days) 29 .…”

Supplementation of a High-Fat Diet with Pentadecylresorcinol Increases the Representation of Akkermansia muciniphila in the Mouse Small and Large Intestines and May Protect against Complications Caused by Imbalanced Nutrition

“…Quick snacks and fast foods enriched with simple sugars, fats, and flavorings create the impression of satiety and food satisfaction. Although there is an assurance that only a prolonged high-fat/high-carbohydrate diet leading to obesity and other metabolic diseases can cause sustainable changes in host and gut microbiota metabolism, in recent years, additional evidence of the crucial influence of a short-term high-fat diet on the gut microbiota and host metabolism has appeared [ 17 , 23 , 24 , 25 ]. It is known that diet-induced changes in the gut microbiome occur rapidly (within days) [ 26 ].…”