Identification of 1-and 3-methylhistidine as biomarkers of skeletal muscle toxicity by nuclear magnetic resonance-based metabolic profiling

被引：46

作者：

Aranibar, Nelly ^{[1
]}

Vassallo, Jeffrey D. ^{[1
]}

Rathmacher, John ^{[2
]}

Stryker, Steve ^{[1
]}

Zhang, Yingru ^{[1
]}

Dai, Jun ^{[1
]}

Janovitz, Evan B. ^{[1
]}

Robertson, Don ^{[1
]}

Reily, Michael ^{[1
]}

Lowe-Krentz, Linda ^{[3
]}

Lehman-McKeeman, Lois ^{[1
]}

机构：

[1] Bristol Myers Squibb Co, Princeton, NJ 08540 USA

[2] Iowa State Univ, Ames, IA 50010 USA

[3] Lehigh Univ, Dept Biol, Bethlehem, PA 18015 USA

来源：

ANALYTICAL BIOCHEMISTRY | 2011年 / 410卷 / 01期

关键词：

Metabolomics; Metabonomics; NMR; GC-MS; 1-Methylhistidine; 3-Methylhistidine; Muscle toxicity; Myopathy; Cerivastatin; Isoproterenol; GENE-EXPRESSION; PROTEIN-TURNOVER; URINARY CREATINE; RAT; CARNOSINE; DAMAGE; ANSERINE; TISSUES; BIOSYNTHESIS; SPECTROSCOPY;

D O I：

10.1016/j.ab.2010.11.023

中图分类号：

Q5 [生物化学];

学科分类号：

070307 [化学生物学];

摘要：

Nuclear magnetic resonance (NMR)-based metabolomic profiling identified urinary 1- and 3-methylhistidine (1- and 3-MH) as potential biomarkers of skeletal muscle toxicity in Sprague-Dawley rats following 7 and 14 daily doses of 0.5 or 1 mg/kg cerivastatin. These metabolites were highly correlated to sex-, dose- and time-dependent development of cerivastatin-induced myotoxicity. Subsequently, the distribution and concentration of 1- and 3-MH were quantified in 18 tissues by gas chromatography-mass spectrometry. The methylhistidine isomers were most abundant in skeletal muscle with no fiber or sex differences observed; however, 3-MH was also present in cardiac and smooth muscle. In a second study, rats receiving 14 daily doses of 1 mg/kg cerivastatin (a myotoxic dose) had 6- and 2-fold elevations in 1- and 3-MH in urine and had 11- and 3-fold increases in 1- and 3-MH in serum, respectively. Selectivity of these potential biomarkers was tested by dosing rats with the cardiotoxicant isoproterenol (0.5 mg/kg), and a 2-fold decrease in urinary 1- and 3-MH was observed and attributed to the anabolic effect on skeletal muscle. These findings indicate that 1 and 3-MH may be useful urine and serum biomarkers of drug-induced skeletal muscle toxicity and hypertrophy in the rat, and further investigation into their use and limitations is warranted. (C) 2010 Elsevier Inc. All rights reserved.

引用

页码：84 / 91

页数：8

共 51 条

[1]

Abe H, 2000, BIOCHEMISTRY-MOSCOW+, V65, P757

[2]

Beta adrenoceptor agonists, clenbuterol, and isoproterenol retard denervation atrophy in rat gastrocnemius muscle: Use of 3-methylhistidine as a marker of myofibrillar degeneration [J].