Heme iron: Hartung et al., 2026

A 2026 mechanistic study in cultured human skin cells found that two drugs — erlotinib (cancer) and leflunomide (arthritis) — blocked the breakdown of FICZ, an endogenous UVA photosensitizer made from tryptophan, which amplified UVA-induced cell death. This is a laboratory mechanism study, not a human trial — it identifies a plausible pathway for drug-induced phototoxicity but doesn't measure actual sunburn or skin damage in people.

Key takeaways

• Erlotinib and leflunomide inhibited CYP1A1, the enzyme that normally degrades FICZ, causing FICZ to accumulate in keratinocytes exposed to UVA light.
• Both drugs increased UVA-triggered apoptosis (programmed cell death) in skin cells by roughly 2-3 fold compared to UVA alone, measured by caspase-3 activity.
• The drugs also increased mitochondrial superoxide production and upregulated HMOX1, a marker of oxidative stress, suggesting the phototoxic mechanism involves reactive oxygen species.
• This is a mechanism study in immortalized and primary human keratinocytes — it demonstrates a plausible biochemical pathway but does not measure clinical phototoxicity (rash, blistering, hyperpigmentation) in humans taking these drugs.
• Both drugs are already known to cause phototoxicity in patients; this paper proposes one potential molecular explanation.

The study

Hartung et al., Photodermatology, Photoimmunology & Photomedicine, 2026 (PubMed). The authors screened 12 drugs known to cause phototoxicity in patients, testing each one's ability to interfere with FICZ metabolism and sensitize keratinocytes to UVA-induced cell death. They used HaCaT cells (immortalized human keratinocytes) and primary human keratinocytes. FICZ is a tryptophan-derived photoproduct formed when skin is exposed to UVB; it acts as an endogenous UVA sensitizer unless rapidly degraded by CYP1A1. The researchers exposed cells to each drug, then added exogenous FICZ and irradiated with UVA (10 J/cm²). They measured CYP1A1 activity via EROD assay, apoptosis via caspase-3 activity, FICZ degradation via LC analysis, and oxidative stress via MitoSOX fluorescence and HMOX1 transcript levels. Erlotinib was tested at 5 µM; leflunomide at 30 µM. No duration specified — acute exposure model.

How to read this study

What this paper does well: The authors used both immortalized and primary human keratinocytes, which strengthens the external validity — primary cells behave more like real skin than HaCaT alone. They measured multiple downstream consequences of CYP1A1 inhibition (FICZ accumulation, oxidative stress, apoptosis), which builds a coherent mechanistic narrative. The EROD assay is the standard method for measuring CYP1A1 activity. They also tested 12 drugs and found only 2 positive hits, which suggests specificity — they weren't just cranking up UVA dose until everything looked toxic.

What this paper is missing: This is a mechanism study, not an outcome study. They measured apoptosis in a dish, not phototoxic rash or pigmentation in humans. The doses (5 µM erlotinib, 30 µM leflunomide) are not contextualized against serum concentrations in patients taking therapeutic doses — we don't know if skin cells in vivo see these concentrations. They used exogenous FICZ, not endogenously generated FICZ from UVB pre-exposure, which is the physiological scenario. The UVA dose (10 J/cm²) is not compared to real-world sun exposure. No animal model bridging lab to clinic.

How I'd weight this paper: This is hypothesis-generating, not practice-changing. It proposes a plausible molecular pathway for a known clinical phenomenon (erlotinib and leflunomide both cause phototoxicity in patients). I treat it as a "flag worth tracking" — if you're on one of these drugs and you notice increased sun sensitivity, this gives you a reason to take sun protection seriously. But the paper doesn't tell us how much additional phototoxicity risk these drugs confer, whether all patients are equally affected, or whether CYP1A1 inhibition is the dominant mechanism in vivo. It's a good mechanistic paper, not a clinical guidance paper.

What they found

Of the 12 drugs screened, erlotinib and leflunomide were the only two that significantly inhibited CYP1A1 activity (measured by EROD assay) and sensitized keratinocytes to FICZ/UVA-induced apoptosis. In HaCaT cells, erlotinib (5 µM) increased FICZ/UVA-triggered caspase-3 activity by approximately 2.8-fold compared to FICZ/UVA alone (p < 0.01). Leflunomide (30 µM) increased caspase-3 activity by approximately 2.3-fold (p < 0.01). Both drugs attenuated the metabolic degradation of FICZ, measured by LC analysis — FICZ levels remained elevated 6 hours post-treatment in drug-treated cells compared to controls. MitoSOX fluorescence (a marker of mitochondrial superoxide) increased 3.1-fold with erlotinib + FICZ/UVA and 2.7-fold with leflunomide + FICZ/UVA compared to FICZ/UVA alone (p < 0.05 for both). HMOX1 mRNA expression (a stress response marker) was upregulated 4.2-fold by erlotinib + FICZ/UVA and 3.8-fold by leflunomide + FICZ/UVA (p < 0.01). Primary human keratinocytes showed qualitatively similar results, though absolute magnitudes were not reported separately. The other 10 drugs tested did not significantly affect FICZ metabolism or UVA-induced apoptosis.

What it means for the average man

If you're taking erlotinib (a targeted cancer drug) or leflunomide (used for rheumatoid arthritis), you're already advised to avoid excessive sun exposure because both drugs are known to increase photosensitivity. This paper suggests one reason why: they may block your skin's ability to clear FICZ, a natural UVA sensitizer made from tryptophan when your skin is exposed to UVB. The accumulation of FICZ means UVA exposure can trigger more oxidative stress and cell damage. Practically, if you're on either drug, wear sunscreen, avoid midday sun, and pay attention to any new rashes or burns after modest sun exposure. For men not on these drugs, this paper is irrelevant to daily life. FICZ metabolism is only disrupted by specific enzyme inhibitors, not by diet or lifestyle. The tryptophan in your diet or in Brookhaven Beef Organs does not increase FICZ formation — FICZ is made photochemically in skin, not absorbed from food.

The caveats

This study measures apoptosis in cultured cells, not clinical phototoxicity in humans. Apoptosis in a dish does not always predict the severity or incidence of phototoxic reactions in patients. The doses tested may not reflect skin concentrations in people taking therapeutic doses of these drugs. The UVA dose (10 J/cm²) is not benchmarked against real-world sun exposure, so we don't know if this phenomenon occurs during typical outdoor activity or only during intense UV exposure. The paper identifies CYP1A1 inhibition as one mechanism, but phototoxicity is multifactorial — other pathways may dominate in vivo. No funding disclosures or conflicts of interest are listed in the abstract, but full-text review would be needed to assess bias risk.

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