Targeted metabolomic profiling indicates structure-based perturbations in serum phospholipids in children with acetaminophen overdose

Abstract

Phospholipids are an important class of lipids that act as building blocks of biological cell membranes and participate in a variety of vital cellular functions including cell signaling. Previous studies have reported alterations in phosphatidylcholine (PC) and lysophosphatidylcholine (lysoPC) metabolism in acetaminophen (APAP)-treated animals or cell cultures. However, little is known about phospholipid perturbations in humans with APAP toxicity. In the current study, targeted metabolomic analysis of 180 different metabolites including 14 lysoPCs and 73 PCs was performed in serum samples from children and adolescents hospitalized for APAP overdose. Metabolite profiles in the overdose group were compared to those of healthy controls and hospitalized children receiving low dose APAP for treatment of pain or fever (therapeutic group). PCs and lysoPCs with very long chain fatty acids (VLCFAs) were significantly decreased in the overdose group, while those with comparatively shorter chain lengths were increased in the overdose group compared to the therapeutic and control groups. All ether linked PCs were decreased in the overdose group compared to the controls. LysoPC-C26:1 was highly reduced in the overdose group and could discriminate between the overdose and control groups with 100% sensitivity and specificity. The PCs and lysoPCs with VLCFAs showed significant associations with changes in clinical indicators of drug metabolism (APAP protein adducts) and liver injury (alanine aminotransferase, or ALT). Thus, a structure-dependent reduction in PCs and lysoPCs was observed in the APAP-overdose group, which may suggest a structure-activity relationship in inhibition of enzymes involved in phospholipid metabolism in APAP toxicity.

Pattern of food, drug and chemical poisoning in Qassim region, Saudi Arabia from January 2017 to December 2017

“…As known, activation charcoal can significantly reduce the overall drug absorption when given shortly and works in patients suffering from acute overdose such as organochlorine insecticides and herbicides [ [39] , [40] , [41] ]. Moreover, it can be used in gastrointestinal decontamination overdose of drugs and toxins, reducing their absorption [ 39 , 42 ]. The oral route is the most common type of exposure reported in the current study ( Table 4 ), and the possible reason is that patients in the age group of 1–5 years were accidental toxicity of drugs or chemicals were the most cases reported [ 30 , 43 ].…”

The Potential Role of Metabolomics in Drug-Induced Liver Injury (DILI) Assessment

“…Attention was paid principally to their links to the DILI and not to the drug causing the event. Among them, few studies addressed the identification of specific markers for DILI prediction or individual susceptibility determination [43,47,[74][75][76] while the vast majority were focused on DILI diagnosis and follow-up [55,[77][78][79][80][81][82][83][84][85][86][87][88][89][90][91][92][93][94][95].…”

“…Phospholipids are important components of the cellular membranes, and they regulate cell functions as signalling molecules. Several of the studies reviewed reported increased or decreased levels of different phospholipids, or changes in their specific structural properties [74,75,79,82,83,[88][89][90][91]. It is possible that these changes might be related to the access or insertion process of the phospholipids to the membrane bilayers during hepatic regeneration.…”

Acetaminophen Interactions with Phospholipid Vesicles Induced Changes in Morphology and Lipid Dynamics

“…Bhattacharyya et al showed the presence of PCs and lysoPCs with very long fatty acids significantly decreased in overdose conditions indicative of a structure-activity relation with enzymes responsible for phospholipid metabolism. 30 Recently, Yamada et al…”