Skin sensitizers enhance superoxide formation by polycyclic aromatic hydrocarbons via the aldo-keto reductase pathway

Abstract

Exposure to combustion-derived airborne polycyclic aromatic hydrocarbons (PAHs) may harm human skin, exacerbate cutaneous inflammatory diseases and accelerate skin aging. The toxicity of PAHs is unleashed upon their metabolic activation by cytochrome P450 (CYP) 1 monooxygenases, resulting in the formation of reactive intermediates that form mutagenic DNA adducts. Moreover, PAHs cause oxidative stress, which is primarily due to aldo-keto reductases (AKRs), such as AKR1C3, which convert CYP1-derived PAH-trans-diols to PAH-catechols. The catechols undergo autooxidation leading to the formation of reactive oxygen species (ROS) and PAH-quinones. The latter are highly reactive, mitotoxic and are reduced back to PAH-catechols, thus facilitating redox cycling. As AKR1C expression is inducible by other NRF2-stimulating chemicals, we tested the hypothesis that co-exposure of HaCaT keratinocytes to skin sensitizers and the PAH benzo[a]pyrene (BaP) enhances ROS formation. We observed a synergistic effect of the skin sensitizers on the BaP-induced expression of the NRF2 target genes heme oxygenase-1, sulfiredoxin-1 and AKR1C3. In fact, co-exposure to the skin sensitizers also enhanced the BaP-induced formation of superoxide anions. Intriguingly, the co-exposure-related ROS formation was abolished upon inhibition of either CYP1A1 or AKR1C3. Testing of additional skin-sensitizing compounds, differing in their mode of action, indicated that especially potent Michael acceptors enhance the toxicity of BaP by increasing AKR1C3 expression and, presumably, downstream BaP-quinone formation. Our study reveals potential health risks associated with the simultaneous exposure to common skin-sensitizing substances and ubiquitous PAHs, and implies a role for NRF2 in mediating PAH toxicity.