title: Nephrotoxicity evaluation of a new cembrane diterpene from Euphorbiae pekinensis Radix with HEK 293T cells and the toxicokinetics study in rats using a sensitive and reliable UFLC-MS/MS.
abstract: (-)-(1S)-15-Hydroxy-18-carboxycembrene, the first cembrane-type diterpenoid found in the family Euphorbiaceae, isolated from Euphorbiae pekinensis Radix, was identified to be nephrotoxic using HEK 293T cells. Tests on cell morphology, cell viability and biochemical markers about oxidation stress were carried out using inverted microscope, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and commercial kits respectively, which proved the diterpene time- and dose-dependently decreased cells proliferation. Besides, a sensitive and robust UFLC-MS/MS method was developed and fully validated to investigate the in vivo behavior in rats of the diterpene after oral administration of Euphorbiae pekinensis Radix extracts at a dosage of 9g/kg. The method showed a good linearity in tested range (3-1500ng/mL) with acceptable accuracy and precision. The recovery of the diterpene was more than 85% and the matrix effect was within ±20%. The toxicokinetics parameters indicate the diterpene reached Cmax quickly and slowly eliminate. The study proved the newly found diterpene was one of the nephrotoxic substances of Euphorbiae pekinensis Radix and revealed its toxicokinetics behavior.
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, China.
authors.forename: Ziying
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Stem Cell Institute, Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, 777 Shelby Interdisciplinary Biomedical Building, 1825 University Boulevard, Birmingham, AL 35294-2182, USA.
authors.forename: Ruowen
authors.initials: R
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, China.
authors.forename: Pengyi
authors.initials: P
authors.lastname: Hou
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, China.
authors.forename: Kaishun
authors.initials: K
authors.lastname: Bi
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, China. Electronic address: cxh_syphu@hotmail.com.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Chen
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002138:Calibration; D002470:Cell Survival / Q000187:drug effects; D002853:Chromatography, Liquid / Q000379:methods*; D004224:Diterpenes / Q000097:blood* / Q000302:isolation & purification / Q000633:toxicity*; D019665:Euphorbiaceae / Q000737:chemistry*; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D057230:Limit of Detection; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: C588371:(-)-(1S)-15-hydroxy-18-carboxycembrene; D004224:Diterpenes
keywords: (−)-(1S)-15-Hydroxy-18-carboxycembrene; Euphorbiae pekinensis Radix; HEK 293T cells; UFLC–MS/MS; toxicokinetics