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
This recent review seems to be pretty thorough:
Aryl Hydrocarbon Receptor in Atopic Dermatitis and Psoriasis
Masutaka Furue, Akiko Hashimoto-Hachiya, Gaku Tsuji
Int J Mol Sci 2019 Nov; 20: 5424. PMCID: PMC6862295
I just glanced through it, but I hope to find time soon to read it 🙂
I can’t answer what would happen with low doses, especially in the context of low-affinity ligands. I would guess nothing of significance, but that’s kind of my bias. There is some evidence to suggest that low-level activation of AHR by high-affinity ligands increases Th17 cells, instead of Tr1 cells. We published those data, but the effect was not very strong and it was not related to topical exposure. Also, if you have a compound that activates AHR enough to induce metabolism of the ligand — who knows what the metabolites might do locally.
Let me know if you want to discuss this further…
on PubMed I entered “AHR contact sensitivity” — and got 36 hits.
Even including UVR-induced immunosuppression… I suppose I could even find more articles if I added “psoriasis” to the mix.
Do you have references handy, demonstrating that lower levels of AHR activation in skin inhibits contact sensitivity and suppresses psoriasis? Do you think that low-level dermal exposure to AHR agonists (doses that modestly elevate AHR activity in skin, e.g ~ 10%) — could be beneficial for psoriasis?
Hi John, I didn’t pay attention to the fact that CYPs are inhibited at high concentrations. I was just thinking about known effects from topical application of several AHR ligands (which would presumably result in increasing CYP activities).
Hi Nancy. Would you predict dermal application of ‘any” inhibitor of CYP1A /CYP1B might have similar beneficial effects, in enhancing the AHR activation?
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. 😊