Detection of <i>in vivo</i> biomarkers of phospholipidosis using NMR‐based metabonomic approaches

Espina, Jaime A; Shockcor, John P.; Herron, William J.; Car, Bruce D.; Contel, Nancy; Ciaccio, Paul J.; Lindon, John C.; Holmes, Elaine; Nicholson, Jeremy K.

doi:10.1002/mrc.907

Cited by 59 publications

(36 citation statements)

References 18 publications

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“…Cholestasis-induced bile duct cell necrosis and subsequent membrane breakdown caused by ANIT and as the result of the serum examinations may account for the elevation of urinary bile acids at 7-55 hours. PAG has been reported to be a potential biomarker for phospholipidosis (Dieterle et al 2006;Espina et al 2001;Idborg-Bjorkman et al 2003;Nicholls et al 2000), and alteration of PAG levels has been found in urinary metabolic fingerprinting for ANIT-induced intrahepatic cholestasis using LC-MS (La et al 2005). PAG is the end product of phenylalanine metabolism in rodents (James et al 1972).…”

Section: Discussionmentioning

confidence: 99%

Urinary Metabolic Fingerprinting for α-naphthylisothiocyanate-induced Intrahepatic Cholestasis in Rats Using Fourier Transform-ion Cyclotron Resonance Mass Spectrometry

et al. 2008

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Urinary metabolic fingerprinting with Fourier transform-ion cyclotron resonance mass spectrometry (FT-ICR MS) was performed to monitor metabolic changes in an α-naphthylisothiocyanate (ANIT)-induced rat model of intrahepatic cholestasis and to investigate the relationships among metabolic changes, histopathology, and blood chemistry. ANIT was administered orally as a single dose of 100 mg/kg. Urine samples were collected predose (-31 to -24 hours) and postdose at 0-7, 7-24, 24-31, 31-48, 48-55, 55-72, and 72-96 hours, and serum samples were collected on days 1, 2, and 4 postdose. Increased levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and total bilirubin were seen on day 2. The negative ion profiles for urine samples collected after 7-24, 24-31, 31-48, and 48-55 hours differed from the predose profile based on principal component analysis. Onset of recovery was observed after 24-31 hours, when the urinary composition reverted toward the predose position. In conclusion, it is possible to monitor the progression of and recovery from drug-induced hepatotoxicity by urinary metabolic fingerprinting with FT-ICR MS and to search for potential biomarkers involved in intrahepatic cholestasis.

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Section: Discussionmentioning

confidence: 99%

Urinary Metabolic Fingerprinting for α-naphthylisothiocyanate-induced Intrahepatic Cholestasis in Rats Using Fourier Transform-ion Cyclotron Resonance Mass Spectrometry

et al. 2008

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“…The technology combines the power of highresolution nuclear magnetic resonance (NMR) techniques with statistical data analysis methods to rapidly evaluate the metabolic status of an animal. Using NMR-based m e t a b o n o m i c s t e c h n i q u e s , u r i n a r y a n d p l a s m a phenylacetylglycine (PAG) has been evaluated to identify biomarkers for PLDsis [83][84][85][86] . Although all the results indicated a perturbation in PAG levels with the induction of PLDsis, the results have been equivocal even using PAG:creatinine ratios.…”

Section: Metabonomicsmentioning

confidence: 99%

Drug-induced Phospholipidosis -Pathological Aspects and Its Prediction

Nonoyama

Fukuda

2008

J Toxicol Pathol

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Drug-induced phospholipidosis (PLDsis) is an excessive accumulation of polar phospholipids in cells or tissues/organs caused by xenobiotics. Numerous drugs and chemicals are capable of inducing the storage disorder in animals and humans; however, despite their diverse pharmacological activities, each of these drugs shares common physicochemical properties: a hydrophobic aromatic ring structure on the molecule and a hydrophilic side chain with a charged cationic amine group and therefore are in the group of cationic amphiphilic drugs. In affected cells the appearance of membrane-bound inclusions, primarily lysosomal in origin, with a lamellar structure (lamellar bodies) is a definitive morphologic hallmark. Massive accumulations can occur in animal tissues such as the lung with little effect on organ function. The inducing drug also accumulates in association with the excess phospholipid. Although these alterations are generally reversible after cessation of drug treatment, PLDsis is of regulatory concern and an issue for drug safety for pharmaceutical companies. Thus, the assessment of potential target organ dysfunction and the identification of clinical biomarkers are important objectives for new drug development. Recent advances in biotechnology such as metabonomics and toxicogenomics have been providing novel tools to elucidate the mechanisms of PLDsis and to establish biomarkers for screening tests in the preclinical stages and for monitoring in the clinical phases in addition to conventional approaches such as morphology (lamellar bodies) and biochemical methods including assays of specific metabolites and phospholipase inhibition. (J Toxicol Pathol 2008; 21: 9-24)

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“…Phospholipidosis is a lipid storage disorder which results in increased numbers of foamy macrophages in lung or liver tissue following a toxicological insult [29,30]. Phenylacetylglycine (PAG) has been reported to be a potential urinary marker for this condition [31][32][33][34]. These previous metabonomic studies employed either nuclear magnetic resonance (NMR) or MS to monitor PAG in urine samples and utilized either internal standards or computational techniques for normalization.…”

Section: Introductionmentioning

confidence: 99%