Abstract
Retinoid induction of epidermal hyperplasia was investigated in hairless mice with synthetic ligands for the retinoic acid (RAR) and retinoid X (RXR) nuclear receptors. Induction of hyperplasia by all-trans retinoic acid and the RAR-specific retinoids TTNPB, tazarotene and AGN 190121 varied over a wide range (ED50 = 0.2–100 nmol/animal in three daily applications). Potency of induction was not directly correlated to receptor-binding affinity, but specificity of action could be demonstrated by inhibition with the high-affinity antagonist of the RARs, AGN 193109. Although RAR is functionally complexed with RXRin vivo, RXR-selective compounds have only weak potency in induction of hyperplasia. The ED50 value of the RXR-selective AGN 191701 was 600 nmol/animal compared with an ED50 value of 0.2 nmol for the structurally similar RAR-selective TTNPB. SR11237 and SR11217, also RXR-selective, each have an ED50 value of >1000 nmol. Unlike RAR-specific retinoids, RXR-selective retinoids cause only very mild skin flaking at high doses. Relative potencies for cumulative topical irritation (flaking and abrasion) of both RAR and RXR ligands were well correlated with epidermal hyperplasia. These data are consistent with RXR as a silent partner in the RAR-RXR heterodimer in skin.
Footnotes
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Send reprint requests to: Dr. S. M. Thacher or Dr. R. A. S. Chandraratna, Allergan, 2525 Dupont Drive, Irvine, CA 92612.
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↵1 Present address: Department of Molecular Biology and Biochemistry, University of California at Irvine, Irvine, CA 92612.
- Abbreviations:
- ODC
- ornithine decarboxylase
- RA
- retinoic acid
- RAR
- retinoic acid receptor
- RARE
- retinoic acid response element
- RXR
- retinoid X receptor
- SDS
- sodium dodecyl sulfate
- TPA
- 12-O-tetradecanoylphorbol-13-acetate
- Received December 11, 1996.
- Accepted April 29, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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