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R115866 inhibits all-trans-retinoic acid metabolism and exerts retinoidal effects in rodents
P Stoppie1, M Borgers, P Borghgraef
1Janssen Research Foundation, Beerse, Belgium.
Abstract:
All-trans-retinoic acid (RA) regulates epithelial differentiation and growth through activation of specific nuclear RA receptors (RARs). Because high-rate metabolism largely impairs the biological efficacy of RA, we have sought for compounds capable of inhibiting the metabolic breakdown of the retinoid. This study identifies R115866 as a novel inhibitor of the cytochrome P450 (CYP)-mediated metabolism of RA. In vitro, nanomolar concentrations of R115866 inhibited the conversion of RA by CYP26, a RA-inducible RA metabolizing enzyme. In vivo, oral administration of R115866 (2.5 mg/kg) to rats induced marked and transient increases of endogenous RA levels in plasma, skin, fat, kidney, and testis. Consistent with its ability to enhance endogenous RA content in tissues, R115866 was found to exert retinoidal activities. Like RA, the title compound: 1) inhibited vaginal keratinization in estrogen-stimulated rats; 2) induced epidermal hyperplasia in mouse ear skin; 3) transformed mouse tail epidermis from a para- to an orthokeratotic skin type; and 4) up-regulated the CYP26 mRNA expression in rat liver. Furthermore, we found that the keratinization-suppressive and CYP26-inducing activities of R115866 could be reversed by concomitant administration of the RAR antagonist, AGN193109. Our data characterize R115866 as a potent, orally active inhibitor of RA metabolism, capable of enhancing RA levels and displaying retinoidal actions. These activities are reversed by RAR antagonism, supporting the idea that the actions of R115866 result from increased availability of endogenous RA and improved RAR triggering.
Insights
Researchers identified R115866, a compound that inhibits the breakdown of all-trans-retinoic acid (RA). This drug increases RA levels, enhancing its beneficial effects on epithelial cells and skin.
Area of Science:
- Biochemistry
- Pharmacology
- Dermatology
Background:
- All-trans-retinoic acid (RA) is crucial for epithelial cell differentiation and growth.
- Rapid metabolism of RA limits its therapeutic efficacy.
- Inhibiting RA metabolism can enhance its biological activity.
Purpose of the Study:
- To identify novel compounds that inhibit the metabolic breakdown of all-trans-retinoic acid (RA).
- To evaluate the efficacy and retinoidal activities of a newly identified RA metabolism inhibitor, R115866.
Main Methods:
- In vitro assays using CYP26 enzyme to assess inhibition of RA conversion.
- In vivo studies in rats involving oral administration of R115866 to measure endogenous RA levels.
- Assessment of retinoidal activities including inhibition of vaginal keratinization and induction of epidermal hyperplasia.
- Analysis of CYP26 mRNA expression and reversal of effects with RAR antagonist AGN193109.
Main Results:
- R115866 potently inhibited RA metabolism by CYP26 in vitro at nanomolar concentrations.
- Oral R115866 administration increased endogenous RA levels across multiple tissues in rats.
- R115866 demonstrated retinoidal activities, mimicking RA's effects on keratinization and epidermal hyperplasia.
- The compound's effects were reversed by RAR antagonism, confirming mechanism via enhanced RA signaling.
Conclusions:
- R115866 is a novel, orally active inhibitor of RA metabolism.
- The compound effectively increases endogenous RA levels and exerts significant retinoidal actions.
- R115866 represents a promising therapeutic strategy for conditions requiring enhanced RA signaling.