Therapeutic Agents with AHR Inhibiting and NRF2 Activating Activity for Managing Chloracne

Abstract

Chloracne is the major skin symptom caused by dioxin intoxication. Dioxin activates the aryl hydrocarbon receptor (AHR)⁻cytochrome p450 1A1 (CYP1A1) system, generates oxidative stress, and induces hyperkeratinization of keratinocytes and sebocytes leading to chloracne. Nuclear factor-erythroid 2-related factor-2 (NRF2) is a master switch that induces the expression of various antioxidative enzymes, such as heme oxygenase-1. Cinnamaldehyde is an antioxidant phytochemical that inhibits AHR⁻CYP1A1 signaling and activates the NRF2⁻antioxidative axis. The cinnamaldehyde-containing Kampo herbal medicine Keishibukuryogan is capable of improving chloracne in Yusho patients who are highly contaminated with dioxin. Agents with dual functions in promoting AHR⁻CYP1A1 inhibition and NRF2 activation may be useful for managing dioxin-related health hazards.

Keywords: Yusho; aryl hydrocarbon receptor; chloracne; dioxin; heme oxygenase-1; nuclear factor-erythroid 2-related factor-2.

Figure 1

Dioxins activate the aryl hydrocarbon receptor (AHR), upregulate the expression of cytochrome P450 1A1 (CYP1A1), and generate reactive oxygen species (ROS) in keratinocytes and sebocytes. The ligation of AHR by dioxins also accelerates terminal differentiation. Oxidative stress and hyperkeratinization are probably responsible for chloracne. Cinnamaldehyde (a functional component of C. cassia) and perillaldehyde (a functional component of P. frutescens) are potent inhibitors of AHR–CYP1A1 signaling. On the other hand, they activate nuclear factor-erythroid 2-related factor-2 (NRF2). NRF2 is a master switch for the cellular antioxidative system. The activation of NRF2 upregulates various antioxidative enzymes, such as heme oxygenase-1 (HMOX1), and neutralizes ROS. These natural phytochemicals are useful for managing chloracne.