LAUSR

BACKGROUND Recently, environmental pollutants have become a concern not only for respiratory organs but also for skin-related human health, because skin is localized at the border between the human body and the external environment and is easily influenced by environmental pollutants. OBJECTIVE Here, we investigated the effects of a novel pantothenic acid (PA) derivative, ethyl 2,4-dicarboethoxy pantothenate (EDCEP), on a diesel particulate extract (DPE) as a representative environmental pollutant that generates reactive oxygen species (ROS) through the activation of aryl hydrocarbon receptor (AHR) signaling. METHODS We characterized the effects of PA and EDCEP on normal human epidermal keratinocytes (NHEKs) exposed to DPE or H2O2 as a general oxidative stress stimulator. Cell viability and intracellular ROS levels were evaluated using the 3-(4,5-dimethyl-2-thiazoyl)-2,5-diphenyltetrazolium bromide (MTT) assay and the 2',7'-dichlorodihydrofluorescein diacetate (DCFDA) assay, respectively. Further, we investigated the substantial effects and the underlying mechanism of EDCEP, which elicited a reduction of intracellular ROS. RESULTS PA and EDCEP restored the decreases of cell viability induced by DPE and also repressed the up-regulation of CYP1A1 mRNA expression induced by DPE. Interestingly, the effects of PA and EDCEP on intracellular ROS levels showed different responses. EDCEP reduced intracellular ROS levels stimulated by DPE or by exposure to H2O2. EDCEP suppressed the secretion of tumor necrosis factor (TNF-α) and reduced the level carbonylated proteins in reconstructed human epidermal equivalents topically treated with DPE. EDCEP up-regulated the mRNA expression levels of nuclear factor E2-related factor 2 (Nrf2), γ-glutamyl cysteine synthase (γ-GCS), heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase-1 (NQO1) and in addition, increased intracellular glutathione (GSH) levels. CONCLUSION EDCEP reduces cellular damage initiated by environmental pollutants by stimulating the intracellular defense system against ROS through the activation of Nrf2, and by interfering with AHR signaling pathway activation.