Antagonism of retinol-induced RNA synthesis: Assessment of retinoid toxicity in cultured retinal pigment epithelium

John D. Gabourel, John M.B. Bradley, Ted S. Acott

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Retinol, complexed to serum retinol binding protein (R-SRBP), stimulated RNA synthesis when added to cultured human retinal pigment epithelium (RPE). At a retinol concentration of 1.0 μglml, the average stimulation ± S.E.M. was 142 ± 5.6% of control. The stimulation was concentration-dependent over the range 0.25-1.5 μg retinol/ml. Stimulation of RNA synthesis was seen with native R-SRBP from pooled human serum and with R-SRBP reconstituted by addition of retinol to apo-SRBP in vitro. Other retinoids complexed with apo-SRBP in vitro failed to stimulate RNA synthesis in this system. Retinol and retinoids, complexed with serum albumin in the culture medium, also failed to stimulate RNA synthesis. Most of the retinoids, when complexed with serum albumin, preferentially antagonized R-SRBP-induced RNA synthesis. At higher concentrations they also inhibited basal RNA synthesis. Retinoids varied in their potency for the preferential antagonism of R-SRBP-induced RNA synthesis. The order of potency was fenretinide > isotretinoin = RO-22-6595 > tretinoin. Etrenitate did not cause a concentration-dependent antagonism of R-SRBP-induced RNA synthesis. Retinol and RO-10-1670 did not exhibit a preferential effect on R-SRBP-induced RNA synthesis. This order of potency roughly parallels the incidence of night blindness and/or excessive glare sensitivity reported when some of these retinoids are used clinically. Retinoid antagonism of R-SRBP-induced RNA synthesis by cultured human RPE suggests that the night blindness associated with high-dose retinoid therapy is a result of retinol antagonism rather than an extension of retinol toxicity and may provide a model to predict the ocular toxicity of new retinoids as they are introduced into clinical trials.

Original languageEnglish (US)
Pages (from-to)251-263
Number of pages13
JournalCutaneous and Ocular Toxicology
Volume9
Issue number4
DOIs
StatePublished - Jan 1 1990

ASJC Scopus subject areas

  • Toxicology

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