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Plasma 2-hydroxyglutarate and hexanoylcarnitine levels are potential biomarkers for skeletal muscle toxicity in male Fischer 344 rats.
J Toxicol Sci 2017; 42(4):385-396JT

Abstract

To identify new candidate biomarkers for skeletal muscle toxicity, an unbiased metabolomic analysis was performed in rats treated with two distinct myotoxicants, cerivastatin (CER) and tetramethyl-p-phenylenediamine (TMPD). Skeletal muscle toxicity was induced in male Fischer 344 rats by administering CER or TMPD and monitored using established endpoints, such as increased plasma creatine kinase (CK) activity and histopathology, and a metabolomic analysis of skeletal muscle and plasma samples. Plasma CK levels in CER-treated rats were markedly elevated at Day 11; however, those in TMPD-treated rats showed a statistically significant decrease at 24 hr after dosing. Light microscopy revealed that vacuolated or necrotic fibers were evident in all CER-treated rats on Day 11, and slightly vacuolated fibers were observed in TMPD-treated rats at 6 and 24 hr after dosing. Metabolomic analysis of the rectus femoris indicated increases in 2-hydroxyglutarate (2HG) in CER-treated rats and hexanoylcarnitine in CER- and TMPD-treated rats. There were also increases in plasma 2HG in CER-treated rats on Days 8 and 11 and in TMPD-treated rats at 24 hr after dosing and increases in plasma hexanoylcarnitine in CER-treated rats on Day 11 and in TMPD-treated rats at 6 and 24 hr after dosing. These experiments demonstrated the potential of plasma 2HG and hexanoylcarnitine as specific and easily detectable biomarkers for skeletal muscle toxicity in rats and demonstrated the value of metabolomics for biomarker detection and identification in toxicological studies.

Authors+Show Affiliations

Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Azabu University. Medicinal Safety Research Laboratories, Daiichi-Sankyo Co., Ltd.Medicinal Safety Research Laboratories, Daiichi-Sankyo Co., Ltd.Medicinal Safety Research Laboratories, Daiichi-Sankyo Co., Ltd.Medicinal Safety Research Laboratories, Daiichi-Sankyo Co., Ltd.Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Azabu University.Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Azabu University.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28717097

Citation

Obayashi, Hisakuni, et al. "Plasma 2-hydroxyglutarate and Hexanoylcarnitine Levels Are Potential Biomarkers for Skeletal Muscle Toxicity in Male Fischer 344 Rats." The Journal of Toxicological Sciences, vol. 42, no. 4, 2017, pp. 385-396.
Obayashi H, Kobayashi N, Nezu Y, et al. Plasma 2-hydroxyglutarate and hexanoylcarnitine levels are potential biomarkers for skeletal muscle toxicity in male Fischer 344 rats. J Toxicol Sci. 2017;42(4):385-396.
Obayashi, H., Kobayashi, N., Nezu, Y., Yamoto, T., Shirai, M., & Asai, F. (2017). Plasma 2-hydroxyglutarate and hexanoylcarnitine levels are potential biomarkers for skeletal muscle toxicity in male Fischer 344 rats. The Journal of Toxicological Sciences, 42(4), pp. 385-396. doi:10.2131/jts.42.385.
Obayashi H, et al. Plasma 2-hydroxyglutarate and Hexanoylcarnitine Levels Are Potential Biomarkers for Skeletal Muscle Toxicity in Male Fischer 344 Rats. J Toxicol Sci. 2017;42(4):385-396. PubMed PMID: 28717097.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Plasma 2-hydroxyglutarate and hexanoylcarnitine levels are potential biomarkers for skeletal muscle toxicity in male Fischer 344 rats. AU - Obayashi,Hisakuni, AU - Kobayashi,Naoko, AU - Nezu,Yoshikazu, AU - Yamoto,Takashi, AU - Shirai,Mitsuyuki, AU - Asai,Fumitoshi, PY - 2017/7/19/entrez PY - 2017/7/19/pubmed PY - 2017/10/6/medline KW - 2-Hydroxyglutarate KW - Biomarkers KW - Hexanoylcarnitine KW - Metabolome KW - Muscle KW - Rats SP - 385 EP - 396 JF - The Journal of toxicological sciences JO - J Toxicol Sci VL - 42 IS - 4 N2 - To identify new candidate biomarkers for skeletal muscle toxicity, an unbiased metabolomic analysis was performed in rats treated with two distinct myotoxicants, cerivastatin (CER) and tetramethyl-p-phenylenediamine (TMPD). Skeletal muscle toxicity was induced in male Fischer 344 rats by administering CER or TMPD and monitored using established endpoints, such as increased plasma creatine kinase (CK) activity and histopathology, and a metabolomic analysis of skeletal muscle and plasma samples. Plasma CK levels in CER-treated rats were markedly elevated at Day 11; however, those in TMPD-treated rats showed a statistically significant decrease at 24 hr after dosing. Light microscopy revealed that vacuolated or necrotic fibers were evident in all CER-treated rats on Day 11, and slightly vacuolated fibers were observed in TMPD-treated rats at 6 and 24 hr after dosing. Metabolomic analysis of the rectus femoris indicated increases in 2-hydroxyglutarate (2HG) in CER-treated rats and hexanoylcarnitine in CER- and TMPD-treated rats. There were also increases in plasma 2HG in CER-treated rats on Days 8 and 11 and in TMPD-treated rats at 24 hr after dosing and increases in plasma hexanoylcarnitine in CER-treated rats on Day 11 and in TMPD-treated rats at 6 and 24 hr after dosing. These experiments demonstrated the potential of plasma 2HG and hexanoylcarnitine as specific and easily detectable biomarkers for skeletal muscle toxicity in rats and demonstrated the value of metabolomics for biomarker detection and identification in toxicological studies. SN - 1880-3989 UR - https://www.unboundmedicine.com/medline/citation/28717097/Plasma_2_hydroxyglutarate_and_hexanoylcarnitine_levels_are_potential_biomarkers_for_skeletal_muscle_toxicity_in_male_Fischer_344_rats_ L2 - https://dx.doi.org/10.2131/jts.42.385 DB - PRIME DP - Unbound Medicine ER -