Phenylacetylglycine, a putative biomarker of phospholipidosis: Its origins and relevance to phospholipid accumulation using amiodarone treated rats as a model

Abstract

Amiodarone was given to male Sprague-Dawley rats at a dose of 150 mg kg(-1) day(-1) for 7 consecutive days to induce phospholipidosis in the lungs of treated rats. Amiodarone was given alone or concurrently with phenobarbitone. Animals given amiodarone had raised total phospholipid in serum, lung and lymphocytes, and elevated lyso(bis)phosphatidic acid (LBPA) in all tissues. Urinary and plasma phenylacetylglycine (PAG) and hepatic portal:aortal phenylacetate (PA) ratio were increased, whereas hepatic phenylalanine hydroxylase (PAH) activity and plasma phenylalanine:tyrosine ratio were not affected. Phenobarbitone treatment increased hepatic total P450 content and induced 7-pentoxyresorufin O-dealkylatian (PROD) activity, as expected, but had no effect on any other biochemical parameter. Plasma amiodarone concentration was reduced in rats co-administered both drugs and phospholipid accumulation in target tissues was attenuated compared with rats treated with amiodarone alone. However, phenobarbitone co-administration failed to alter the magnitude of response with regards to urinary PAG excretion and plasma concentration of its precursors after amiodarone treatment. Increased intestinal absorption of PAG precursors probably resulted in the raised urinary PAG after amiodarone treatment. Urinary PAG correlated weakly with serum, lymphocyte and lung phospholipids. However, urinary PAG excretion was similar in rats dosed solely with amiodarone or in combination with phenobarbitone, despite the fact that the degree of phospholipid accumulation was far less in rats given the combined treatment. Nevertheless, urinary PAG was raised only in animals exhibiting abnormal phospholipid accumulation in target tissues and may thus be useful as a surrogate biomarker for phospholipidosis.

Assessment of amiodarone-induced phospholipidosis in chimeric mice with a humanized liver

“…Ion images can include other endogenous molecules corresponding to the PhC mass. Additional assessments with model compounds related to species differences of DIPL and drug metabolism, other than amiodarone, may be needed to identify human-or mouse-specific biomarkers including phospholipids through IMS, although phenylacetylglycine and di-docosahexaenoyl-bis(monoacylglycerol) phosphate are biomarkers induced by amiodarone (Delaney et al, 2004;Mesens et al, 2012).…”

“…We used chimeric mice (male, 11 to 12-week old) with the middle replacement index (RI) of human hepatocytes (60.8-65.4%), in which the occupancy ratio of the human hepatic region to the total area was estimated based on the human albumin concentration in the blood. Sirajudeen et al (2002) and Delaney et al (2004) reported that total serum and liver phospholipid levels increase after repeated oral administration of 150 and 175 mg/kg amiodarone for 7 and 14 days in rats, respectively. Lipid accumulation was histologically observed in mouse livers administered with 40 mg/kg oral amiodarone for 4 days (Vitins et al, 2014).…”

Metabolic analysis of the effect of rheum on a taurocholate-induced acute pancreatitis rat model

“…Therefore, the increase of TMAO in the serum samples from the AP and medication groups was induced by the digestion of pancreatic tissue. Hippuric acid and PAG are usually produced by intestinal bacteria (Delaney et al, 2004;Phipps et al, 1998), and PAG is the end product of phenylalanine in rodents (James et al, 1972). The increase in the levels of hippuric acid and PAG in the AP groups indicated intestinal bacteria entering the blood, whereas the remaining hippuric acid in the medication groups indicated inhibition by rheum.…”

Increased levels of urinary phenylacetylglycine associated with mitochondrial toxicity in a model of drug-induced phospholipidosis

“…uPAG has also been shown to be affected by parasitic infection [GarciaPerez et al 2010] and dietary intake [O'Sullivan et al 2011]. Several subsequent studies of urinary metabolites in rats with PLD induced by amiodarone reported increases in uPAG [Delaney et al 2004;Dieterle et al 2006;Hasegawa et al 2007]. PAG has therefore been suggested as a surrogate marker for PLD.…”

“…PAG is published as a marker for phospholipidosis [Garcia-Perez et al 2010;Espina et al 2001;Robertson et al 2010] even after single compound administration [Nicholls et al 2000;Delaney et al 2004;Hasegawa et al 2007], but the predictivity as a marker is critically discussed within the expert field and it has not been linked to mitochondrial toxicity. In a model tested to detect phospholipidosis with metabonomics techniques after single compound administration using 20 non-phospholipidogenic and 17 phospholipidogenic compounds, Lienemann and colleagues concluded that the induction of phospholipidosis by the test compounds could not be predicted using NMR-based urine analysis or the previously published biomarker PAG [Lienemann et al 2008].…”