title: Coumarin derivatives, but not coumarin itself, cause skin irritation via topical delivery.
abstract: Coumarin and its derivatives are widely employed as a fragrance in cosmetics and skin care products. The skin absorption level and possible disruption to the skin by topical application of coumarins were evaluated in this study. Percutaneous absorption of osthole, daphnoretin, coumarin, byakangelicin, and 7-hydroxycoumarin was assessed in vitro and in vivo. Skin physiology measurements and immunoblotting were utilized as methodologies for validating toxicity. The relationship between structures and permeation/toxicity of coumarins was elucidated. Both equimolar concentration and saturated solubility in 30% ethanol were used as the applied dose. Osthole with the most lipophilic characteristic demonstrated the greatest skin accumulation, followed by coumarin and 7-hydroxycoumarin. Coumarin was the permeant with the highest flux across the skin. The trend of in vivo deposition was consistent with that of the in vitro profiles. Skin uptake of osthole was 8-fold higher than that of coumarin. Hair follicles played a significant role as a pathway for transport of coumarin according to the examination of follicular accumulation. Osthole and 7-hydroxycoumarin slightly, but significantly, enhanced transepidermal water loss after a consecutive 5-day administration. The immunoblotting profiling verified the role of proliferation in skin damage induced by osthole, byakangelicin, and 7-hydroxycoumarin. The proliferation-related proteins examined in this work included glucose-regulated proteins, cytokeratin, and C-myc. Daphnoretin and coumarin showed a negligible alteration on protein biomarkers. The experimental results suggested that skin irritation caused by coumarins was mainly derived from the analogs but not from coumarin itself.
authors.affiliation: School of Traditional Chinese Medicine, Chang Gung University, Kweishan, Taoyuan, Taiwan; Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Kweishan, Taoyuan, Taiwan.
authors.forename: Tai-Long
authors.initials: TL
authors.lastname: Pan
authors.affiliation: School of Traditional Chinese Medicine, Chang Gung University, Kweishan, Taoyuan, Taiwan; Research Center for Industry of Human Ecology, Chang Gung University of Science and Technology, Kweishan, Taoyuan, Taiwan.
authors.forename: Pei-Wen
authors.initials: PW
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Ibrahim A
authors.initials: IA
authors.lastname: Aljuffali
authors.affiliation: Natural Products Laboratory, Graduate Institute of Natural Products, Chang Gung University, Kweishan, Taoyuan, Taiwan.
authors.forename: Yann-Lii
authors.initials: YL
authors.lastname: Leu
authors.affiliation: Pharmaceutics Laboratory, Graduate Institute of Natural Products, Chang Gung University, Kweishan, Taoyuan, Taiwan; Chronic Diseases and Health Promotion Research Center, Chang Gung University of Science and Technology, Kweishan, Taoyuan, Taiwan.
authors.forename: Yi-Yun
authors.initials: YY
authors.lastname: Hung
authors.affiliation: Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Kweishan, Taoyuan, Taiwan; Pharmaceutics Laboratory, Graduate Institute of Natural Products, Chang Gung University, Kweishan, Taoyuan, Taiwan; Graduate Institute of Health Industry Technology, Chang Gung University of Science and Technology, Kweishan, Taoyuan, Taiwan. Electronic address: fajy@mail.cgu.edu.tw.
authors.forename: Jia-You
authors.initials: JY
authors.lastname: Fang
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival; D003374:Coumarins / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D018859:Hair Follicle / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007509:Irritants / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D010539:Permeability; D015203:Reproducibility of Results; D012867:Skin / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D012869:Skin Absorption; D023422:Skin Irritancy Tests; D013329:Structure-Activity Relationship; D013552:Swine; D014870:Water Loss, Insensible
chemical_list: D015415:Biomarkers; D003374:Coumarins; D007509:Irritants; C030123:coumarin
keywords: Coumarins; Percutaneous absorption; Proliferation; Protein; Skin irritation