title: Pyranocoumarin Tissue Distribution, Plasma Metabolome and Prostate Transcriptome Impacts of Sub-Chronic Exposure to Korean Angelica Supplement in Mice.
abstract: Herbal products containing Korean Angelica gigas Nakai (AGN) root extract are marketed as dietary supplements for memory enhancement, pain killing, and female menopausal symptom relief. We have shown the anticancer activities of AGN supplements in mouse models. To facilitate human anticancer translational research, we characterized the tissue distribution of AGN marker pyranocoumarin compounds decursin (D) and decursinol angelate (DA) ([Formula: see text]% in AGN) and their metabolite decursinol (DOH), assessed the safety of sub-chronic AGN dietary exposure in mice, and explored its impact on plasma aqueous metabolites and the prostate transcriptome. The data show that after a gavage dose, plasma contained readily detectable DOH, but little D and DA, mirroring patterns in the liver. Extra-hepatic tissues retained greater levels of DA and D than the liver did. For sub-chronic exposures, male mice were provided ad libitum AIN93M-pellet diets with 0.5 and 1% AGN for six weeks. No adverse effects were observed on the plasma biochemistry markers of liver and kidney integrity in spite of their enlargement. Histopathological examinations of the liver, kidney and other visceral organs did not reveal tissue abnormalities. Metabolomic assessment of plasma from mice fed the 1%-AGN diet suggested metabolic shifts of key amino acids especially in the methionine-cysteine cycle, purine cycle, and glycolysis-citrate cycle. Prostate transcriptomic profiling identified gene signature changes in the metabolisms of drugs, lipids and cellular energetics, neuro-muscular features, immunity and inflammation, and tumor suppressor/oncogene balance. The safety profile was corroborated with a daily [Formula: see text] injection of AGN extract (100-300[Formula: see text]mg/kg) for four weeks, which resulted in much greater systemic pyranocoumarin exposure than the dietary route did.
authors.affiliation: * Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave, Silver Spring, MD 20993, USA.
authors.forename: Jinhui
authors.initials: J
authors.lastname: Zhang
authors.affiliation: * Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave, Silver Spring, MD 20993, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: † Department of Biomedical Sciences, Texas Tech University Health Sciences Center, School of Pharmacy, Amarillo, Texas, USA.
authors.forename: Suni
authors.initials: S
authors.lastname: Tang
authors.affiliation: † Department of Biomedical Sciences, Texas Tech University Health Sciences Center, School of Pharmacy, Amarillo, Texas, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: ‡ Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, School of Pharmacy, Abilene, Texas, USA.
authors.forename: Maciej
authors.initials: M
authors.lastname: Markiewski
authors.affiliation: § Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Chengguo
authors.initials: C
authors.lastname: Xing
authors.affiliation: ¶ Department of Pharmacology and Cancer Institute, Penn State College of Medicine, 500 University Drive, PO Box 850 MC R130, Hershey, PA 17033, USA.
authors.forename: Cheng
authors.initials: C
authors.lastname: Jiang
authors.affiliation: ¶ Department of Pharmacology and Cancer Institute, Penn State College of Medicine, 500 University Drive, PO Box 850 MC R130, Hershey, PA 17033, USA.
authors.forename: Junxuan
authors.initials: J
authors.lastname: Lü
mesh_terms: D029969:Angelica / Q000737:chemistry*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic; D001578:Benzopyrans / Q000378:metabolism; D002087:Butyrates / Q000378:metabolism; D019587:Dietary Supplements; D005260:Female; D007274:Injections, Intraperitoneal; D008297:Male; D055442:Metabolome; D008810:Mice, Inbred C57BL; D010936:Plant Extracts / Q000008:administration & dosage / Q000302:isolation & purification / Q000494:pharmacology*; D018517:Plant Roots / Q000737:chemistry; D011467:Prostate / Q000378:metabolism*; D039681:Pyranocoumarins / Q000378:metabolism*; D014018:Tissue Distribution; D059467:Transcriptome
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D001578:Benzopyrans; D002087:Butyrates; D010936:Plant Extracts; D039681:Pyranocoumarins; C101278:decursin
keywords: Angelica gigas Nakai; Decursin; Decursinol; Decursinol Angelate; Plasma Metabolome; Safety Assessment; Tissue Distribution