Comparison of urinary and serum levels of di-22:6-bis(monoacylglycerol)phosphate as noninvasive biomarkers of phospholipidosis in rats

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• 作者：Karol L. Thompson ; Jun Zhang ; Sharron Stewart ; Barry A. Rosenzweig ; Katherine Shea ; Daniel Mans ; Thomas Colatsky
• 关键词：ALT ; alanine aminotransferase ; APAP ; acetaminophen ; AUC ; area under the curve ; CAD ; cationic amphiphilic drug ; DEAEH ; 4 ; 4&prime ; -diethylaminoethoxyhexestrol dihydrochloride ; di-22 ; 6-BMP ; di-docosahexaenoyl bis(monoacylglycerol)phosphate ; GPI ; general pho
• 刊名：Toxicology Letters
• 出版年：2012
• 出版时间：3 September, 2012
• 年：2012
• 卷：213
• 期：2
• 页码：285-291
• 全文大小：428 K

文摘

Phospholipidosis (PLD), an abnormal accumulation of phospholipids within tissues, is observed during the preclinical testing of many pharmaceutical drugs. Diagnosis of PLD is currently based on morphologic criteria. An understanding of the clinical incidence of PLD and its possible relationship to adverse drug reactions has been hampered by the absence of noninvasive biomarkers for PLD. The uncommon phospholipid di-docosahexaenoyl bis(monoacylglycerol) phosphate (di-22:6-BMP) has been proposed as a potential urinary biomarker for PLD, but data on the utility of serum di-22:6-BMP measurements in diagnosing PLD is more limited. In this report, we compared the performance of serum and urinary di-22:6-BMP as biomarkers for PLD in rats treated with the PLD-inducing drugs amiodarone and 4,4¡ä-diethylaminoethoxyhexestrol dihydrochloride or the hepatotoxicant acetaminophen (APAP). Serum levels of di-22:6-BMP showed a higher correlation to a generalized PLD incidence score than did levels in urine, but were unexpectedly elevated in rats with marked levels of APAP-induced liver necrosis. When samples were filtered based on serum ALT or liver histopathology thresholds, the diagnostic accuracy of serum di-22:6-BMP for PLD improved to the high level observed for urinary di-22:6-BMP without sample exclusion. These data help define the potential context-of-use of serum di-22:6-BMP as a non-clinical biomarker of PLD.