title: Identification of 1- and 3-methylhistidine as biomarkers of skeletal muscle toxicity by nuclear magnetic resonance-based metabolic profiling.
abstract: 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 1mg/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 1mg/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 (0.5mg/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.
authors.affiliation: Bristol-Myers Squibb, Princeton, NJ 08540, USA. nelly.aranibar@bms.com
authors.forename: Nelly
authors.initials: N
authors.lastname: Aranibar
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Vassallo
authors.forename: John
authors.initials: J
authors.lastname: Rathmacher
authors.forename: Steve
authors.initials: S
authors.lastname: Stryker
authors.forename: Yingru
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jun
authors.initials: J
authors.lastname: Dai
authors.forename: Evan B
authors.initials: EB
authors.lastname: Janovitz
authors.forename: Don
authors.initials: D
authors.lastname: Robertson
authors.forename: Michael
authors.initials: M
authors.lastname: Reily
authors.forename: Linda
authors.initials: L
authors.lastname: Lowe-Krentz
authors.forename: Lois
authors.initials: L
authors.lastname: Lehman-McKeeman
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism / Q000652:urine; D003401:Creatine / Q000378:metabolism / Q000652:urine; D004305:Dose-Response Relationship, Drug; D005260:Female; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008297:Male; D055432:Metabolomics / Q000379:methods*; D008762:Methylhistidines / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism*; D009135:Muscular Diseases / Q000139:chemically induced / Q000378:metabolism / Q000652:urine; D011725:Pyridines / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D015415:Biomarkers; D008762:Methylhistidines; D011725:Pyridines; C028120:1-methylhistidine; C086276:cerivastatin; C028118:3-methylhistidine; D003401:Creatine