A comparative study of the effect of pigment on drug toxicity in human choroidal melanocytes and retinal pigment epithelial cells.
The aim of this study was to investigate whether the presence of pigment affects the sensitivity of pigmented cells of the eye, retinal pigment epithelium (RPE) and choroidal melanocytes (CMs) to the cytotoxic effects of xenobiotic drugs. Two approaches were used to compare pigmented versus unpigmented cells: RPE cells were repigmented by phagocytosis of synthetic melanin; UVB irradiation was used to induce an increase in pigment in both RPE and CMs. Three drugs known to induce toxicity in the eye, tamoxifen, chloroquine and thioridazine, were used to assess the sensitivity of cells to xenobiotic drugs. RPE cells were more resistant than CMs to the cytotoxic effects of all three drugs by a factor of 5-fold for tamoxifen, 7-fold for thioridazine and 30-fold for chloroquine. When RPE cells were repigmented using synthetic melanin, their sensitivity to tamoxifen was unchanged, they showed a slightly improved response to thioridazine (after 3 days of incubation with this drug), but they showed greatly increased toxicity to chloroquine (after 1 and 3 days of exposure to the drug), suggesting accumulation of this latter drug on the synthetic melanin. UVB irradiation was used to achieve an increase in the pigment content of both RPE and CMs. CMs were much more sensitive to UVB than RPE cells. CMs appeared to synthesise pigment via DOPA oxidase activity; RPE cells showed an increase in fluorescent material independent of any detectable DOPA oxidase activity. Irrespective of the nature of the pigment that UVB induced in melanocytes and RPE cells, their subsequent response to thioridazine and chloroquine was unchanged by the presence of this pigment.
Eves
P
P
Division of Clinical Sciences, Clinical Sciences Centre, Northern General Hospital, Sheffield, United Kingdom.
Smith-Thomas
L
L
Hedley
S
S
Wagner
M
M
Balafa
C
C
Mac Neil
S
S
D000962:Antimalarials / Q000633:toxicity; D014150:Antipsychotic Agents / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D002738:Chloroquine / Q000633:toxicity*; D002829:Choroid / Q000166:cytology; D004965:Estrogen Antagonists / Q000633:toxicity; D005434:Flow Cytometry / Q000379:methods; D006801:Humans; D008543:Melanins / Q000138:chemical synthesis / Q000502:physiology; D008544:Melanocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D014442:Monophenol Monooxygenase / Q000378:metabolism; D010587:Phagocytosis; D010857:Pigment Epithelium of Eye / Q000187:drug effects* / Q000473:pathology / Q000528:radiation effects; D010858:Pigmentation; D010860:Pigments, Biological / Q000502:physiology*; D012160:Retina / Q000166:cytology; D013629:Tamoxifen / Q000633:toxicity*; D013881:Thioridazine / Q000633:toxicity*; D014466:Ultraviolet Rays; D015262:Xenobiotics / Q000633:toxicity
D000962:Antimalarials; D014150:Antipsychotic Agents; D004965:Estrogen Antagonists; D008543:Melanins; D010860:Pigments, Biological; D015262:Xenobiotics; D013629:Tamoxifen; D002738:Chloroquine; D014442:Monophenol Monooxygenase; D013881:Thioridazine