The utilization of sulfur amino acid in the mercapturate pathway to detoxify maximal therapeutic dose of acetaminophen is associated with glutathione and protein homeosteny in adult rats

Abstract

It has been shown that sulfur amino acids (SAA) used for acetaminophen (APAP) detoxification, as sulfate conjugate and mercapturate (glutathione (GSH) conjugation), can represent a significant part of dietary SAA and lead to GSH and protein homeosteny. We determined the metabolic alterations induced by APAP detoxification in adult rats receiving daily the half or maximal therapeutic French dose for human. APAP was provided in a 16% protein diet at the dose of 0 (control, n=6), 0.5 (n=7) or 1% (n=7) for 17 days. 1% APAP reduced nitrogen balance (36%), weights of small intestine (13%) and gastrocnemius (7%), hepatic, muscular and intestinal GSH levels by 56%, 20% and 8%, respectively. These parameters were unchanged by 0.5% APAP. Urinary sulfate conjugate was independent of APAP dose, whereas mercapturate of APAP increased from 3% to 14% of ingested SAA in 0.5 and 1% APAP, respectively. Posttranslational alterations of hepatic proteins (APAP protein adducts and modified residues, assessed by target and global metabolomics) occurred with 0.5% APAP and to a larger extent with 1% APAP. Variations of all studied parameters occurred with the APAP dose that is accompanied by upper use of SAA. Further experiments are required to determine if cysteine supplementation could preserve the structure of hepatic proteins at moderate APAP dose, and limit all metabolic alterations occurring with the APAP dose at 1% of the diet.