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  3. Systematic establishment of the relationship between skin absorption and toxicity of furanoids via in silico, in vitro, and in vivo assessments

Systematic establishment of the relationship between skin absorption and toxicity of furanoids via in silico, in vitro, and in vivo assessments

  • Environ Res. 2024 Nov 15:261:119757. doi: 10.1016/j.envres.2024.119757.
Yin-Ku Lin 1,  Chien-Yu Hsiao 2,  Chih-Jung Chen 3,  Ahmed Alalaiwe 4,  Chin Lee 5,  Tse-Hung Huang 6,  Jia-You Fang 7
Affiliations

Affiliations

  • 1 Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Linkou and Keelung, Taiwan; School of Traditional Chinese Medicine, Chang Gung University, Kweishan, Taoyuan, Taiwan.
  • 2 Department of Nutrition and Health Sciences, Chang Gung University of Science and Technology, Kweishan, Taoyuan, Taiwan; Research Center for Food and Cosmetic Safety and Research Center for Chinese Herbal Medicine, Chang Gung University of Science and Technology, Kweishan, Taoyuan, Taiwan; Aesthetic Medical Center, Department of Dermatology, Chang Gung Memorial Hospital, Linkou, Taiwan.
  • 3 Department of Pathology and Laboratory Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; School of Medicine, Chung Shan Medical University, Taichung, Taiwan; Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan.
  • 4 Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al Kharj, Saudi Arabia.
  • 5 Pharmaceutics Laboratory, Graduate Institute of Natural Products, Chang Gung University, Kweishan, Taoyuan, Taiwan.
  • 6 Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Linkou and Keelung, Taiwan; School of Traditional Chinese Medicine, Chang Gung University, Kweishan, Taoyuan, Taiwan; Research Center for Food and Cosmetic Safety and Research Center for Chinese Herbal Medicine, Chang Gung University of Science and Technology, Kweishan, Taoyuan, Taiwan; Department of Chemical Engineering and Graduate Institute of Biochemical Engineering, Ming Chi University of Technology, New Taipei City, Taiwan; Department of Traditional Chinese Medicine, Xiamen Chang Gung Memorial Hospital, Xiamen, China. Electronic address: kchuang@cgmh.org.tw.
  • 7 Research Center for Food and Cosmetic Safety and Research Center for Chinese Herbal Medicine, Chang Gung University of Science and Technology, Kweishan, Taoyuan, Taiwan; Pharmaceutics Laboratory, Graduate Institute of Natural Products, Chang Gung University, Kweishan, Taoyuan, Taiwan; Department of Anesthesiology, Chang Gung Memorial Hospital, Linkou, Taiwan. Electronic address: fajy@mail.cgu.edu.tw.
PMID: 39128665 DOI: 10.1016/j.envres.2024.119757
Abstract

Furanoids are a class of contaminants prevalent in both airborne and occupational environments, with potential health implications through inhalation, oral ingestion, and skin penetration. Given their diminutive molecular size, there is a presumption that furanoids can readily permeate the skin. To systematically explore this presumption, we investigated the skin absorption and toxicity of a series of furans (furfuryl alcohol, furfuryl acetate, furfural, methyl 2-furoate, and 5-methylfurfural) using in silico, in vitro, and in vivo models. The in vitro permeation test (IVPT) from neat and aqueous suspension (5 mM) of furans demonstrated a facile absorption through pig and nude mouse skins. The lipophilicity of furans significantly influenced skin deposition, with higher lipophilicity displaying greater deposition. However, an opposing trend emerged in the receptor compartment accumulation. In barrier-defective skin simulating atopic dermatitis (AD) and psoriasis, enhanced deposition occurred with more hydrophilic furans but not with the more lipophilic ones. In the cell-based study, furanoids induced the proliferation of keratinocytes and skin fibroblasts except for the compounds with the aldehyde group (furfural and 5-methylfurfural). Both furfuryl acetate and 5-methylfurfural activated keratinocytes via the overexpression of COX-2 and PGE2 by 1.5‒2-fold. This stimulation involved the mitogen-activated protein kinase (MAPK) signaling pathway. For the in vivo mouse skin treatment, we selected furfuryl acetate (hydrophilic) and 5-methylfurfural (lipophilic). Both furans showed different patterns of skin lesions, where repeated application of furfuryl acetate caused epidermal hyperplasia and scaling, while 5-methylfurfural predominantly evoked skin inflammation and barrier disintegration. Toxicokinetics analysis revealed a higher plasma concentration of topically applied furfuryl acetate than that of the 5-methylfurfural (5.04 versus 2.34 nmol/ml), resulting in the mild injury of furfuryl acetate-treated peripheral organs. Conversely, no notable adverse effects on organs were observed for the 5-methylfurfural. This study established the relationship between cutaneous absorption and the toxicity of furans following skin exposure.

Keywords

Furanoid; Inflammation; Proliferation; Skin absorption; Structure-permeation relationship; Toxicity.

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