Gene Expression Profiling and Phototoxicity in Adults and Children Exposed to Ultraviolet Radiation

OBJECTIVES:

Primary

- Determine the global gene expression profiles of phototoxic skin reactions in healthy
volunteers treated with doxycycline and compare these expression profiles with the
expression profiles of skin exposed to ultraviolet radiation in the absence of
doxycycline.

- To investigate the effects of the doxycycline alone in the skin of healthy volunteers
previously categorized as phototoxic and non-phototoxic

- Characterize voriconazole-related phototoxicity in participants utilizing phototesting.

- Determine if participants with phototoxicity related to voriconazole receive reasonable
phototoxic protection from the use of sunblock.

Secondary

- Determine the relationship between voriconazole phototoxicity and pharmacogenomics
(cytochrome P450 isoenzyme CYP2C19).

- Determine the role of UVA (320-400 nm) and visible light in phototoxicity reactions
associated with doxycycline and voriconazole.

OUTLINE: This is a pilot study.

- Healthy volunteers: On day 1, participants undergo baseline phototesting comprising
solar-simulated ultraviolet radiation (ssUVR), UVA, and visible light exposures on
sun-protected skin and pre- and post-exposure photographic documentation. On day 2,
participants undergo additional photographic documentation, colorimeter measurements of
non-exposed laterally adjacent skin and post-exposure sites with minimal visible
erythema, and biopsies (using a modified shave biopsy technique) of exposed and
unexposed skin. Participants receive oral doxycycline twice daily on days 3-5. On day
6, participants receive the final dose (7th dose of oral doxycycline) followed 2 hours
later by blood draws (for liver function testing and pharmacologic analyses).
Participants also undergo phototesting comprising ssUVR, UVA, and visible light
exposure and pre- and post-exposure photographic documentation. On day 7, participants
undergo additional photographic documentation, colorimeter measurements, and biopsies
of exposed and unexposed skin.

Skin biopsies are examined by gene expression microarray studies.

- Participants currently receiving, previously received, or scheduled to receive
voriconazole: On days 1 and 2, participants undergo baseline phototesting, pre- and
post-exposure photographic documentation, and colorimeter measurements as in healthy
volunteers. Biopsies are optional. On or about day 10 (after ≥ 7 days of receiving oral
voriconazole), participants receive a dose of oral voriconazole followed 1 hour later
by blood draws (for liver function testing and pharmacologic analyses). Participants
also undergo sunscreen phototesting comprising ssUVR, UVA, and visible light exposure
on skin protected with an over-the-counter sunscreen and sunblock, and pre- and
post-exposure photographic documentation. On day 11, participants undergo additional
photographic documentation, colorimeter measurements, and optional biopsies.

Blood is examined for cytochrome P450 genotyping (CYP2C19 gene variations) via restriction
fragment-length polymorphism-based techniques or nucleotide sequencing.

PROJECTED ACCRUAL: A total of 195 participants will be accrued for this study.