This topic involves gene-environment interactions. Octinoxate (a sunscreen) is the “environmental signal”, and genetic activation via aryl hydrocarbon receptor (AHR)-signaling represents the “response to the signal.”
We are constantly exposed to varying levels of ultraviolet radiation (UVR) from the sun — which includes two main wavelength differences, UVA (320–400 nm) and UVB (280–320 nm). This exposure elicits beneficial effects (e.g. enhancing our vitamin D levels); however, UVB exposure is well known to cause increased risk of skin cancer (via DNA mutagenic lesions). To decrease this risk, sunscreens are now widely used to protect our skin. Commercially available sunscreens usually contain a mixture of organic and/or inorganic compounds that function as UVR filters (by either absorbing or reflecting UVR away from skin). Despite this protection, studies suggest UVR filters do not stay exclusively on the skin surface (i.e. several sunscreens are known to penetrate through the outer layers of epidermis and reach systemic circulation at measurable concentrations).
In fact, it recently has been shown that, under maximal application conditions, plasma levels of selected UVR sunscreens “exceeded FDA-allowed thresholds in specific toxicological tests.” Authors [see attached article] believe it is important to determine if UVR filters have significant “off-target effects” (i.e. affecting pathways that are better off not being affected) — which could negatively impact human health; this is particularly important for babies and young children, because their skin is thinner than that of adults and usually contains lower levels of melanin (pigment).
Many UVR filters are hydrophobic and contain aromatic rings — making them potential candidates for interacting with AHR, a ligand-activated transcription factor that regulates expression of various enzymes involved in metabolizing both foreign and endogenous compounds (and also has been shown to be important in immune function and skin integrity). In fact, AHR-CYP1 signaling, which is already active in embryonic stem cells, appears to be involved in virtually every cell-type of the body, participating in many dozens of critical-life functions [reviewed in Progr Lipid Res 2017; 67: 38-57].
Authors [see attached article] demonstrated that the UVR sunscreen, octinoxate, potentiated the ability of a known AHR ligand, 6-formylindolo[3,2-b]carbazole (FICZ), to activate AHR. Co-treatment of HaCaT cells (a human immortalized keratinocyte cell line — commonly used in keratinocyte and skin studies) — with octinoxate and FICZ induced cytochrome P450 1A1 (CYP1A1) and P4501B1 (CYP1B1) mRNA transcripts — in an AHR-dependent fashion. Octinoxate was also shown to be an inhibitor of CYP1A1 and CYP1B1 enzyme activity, but with IC50 values of approximately 1 mM and 586 nM, respectively (which are not in a physiologically relevant range, in the eyes of these GEITP pages). Topical application of octinoxate and FICZ on mouse skin also increased CYP1A1 and CYP1B1 mRNA levels. Thus, octinoxate is able to activate AHR-signaling, as well as inhibiting CYP1A1 and CYP1B1 enzyme function at very high concentrations — which (the authors say) “may have important downstream consequences for metabolism of various compounds and skin integrity.” Octinoxate interference with critically-important AHR-dependent pathways, however, is probably far more important than “inhibition of enzyme activities.” 😊
Toxicol Sci Sept 2020; 177: 188-201
I would predict that epidermal administration of Octinoxate might result in beneficial effects — because topical application of AHR ligands is known to inhibit contact hypersensitivity, as well as to suppress development of psoriasis. 😊