Identification of the MMP-1 regulation mechanism of benzopyrene, polycyclic aromatic hydrocarbons in foods

Benzo[a]pyrene-7,8-diol-9,10-epoxide (B[a]PDE) has been reported to cause various pathological lesions in humans via activation of the aryl hydrocarbon receptor (AhR) pathway. However, the molecular mechanism by which B[a]PDE regulates signaling pathways during skin aging remains unclear. The present study investigated the effects of B[a]PDE on the expression of matrix metalloproteinase-1 (MMP-1), which is a major enzyme responsible for collagen damage, and its regulation of skin aging-related signaling pathways in HaCaT human keratinocyte cells. MMP-1 expression was increased by B[a]PDE treatment, and mitogen-activated protein kinase (MAPK) inhibitors suppressed B[a]PDE-induced MMP-1 expression. Furthermore, a-naphthoflavone (a-NF, AhR antagonist), PP2 (c-Src inhibitor), and gefitinib (EGFR inhibitor) attenuated the B[a]PDE-induced phosphorylation of and p38 and their upstream kinases such as c-Raf, MEK, and MKK3/6. These results suggest that AhR, c-Src, and epidermal growth factor receptor (EGFR) activations are necessary for B[a]PDE-induced MMP-1 upregulation by modulation of MAPK pathway activation. B[a]PDE also stimulates the phosphorylation of ERK via c-Src-dependent EGFR transactivation. These results demonstrate a novel mechanism by which B[a]PDE induces MMP-1 expression through the activation of AhR, c-Src, and EGFR in non-genetic pathways. Thus, it is indicated that the molecular mechanisms of MMP-1 expression by B[a]PDE-activated AhR play an important role in promoting skin aging.