Pharmacokinetics of Topically Applied Radiolabeled Retinoids in Hairless Mouse Epidermis and Dermis After Single Applications

Connor, Michael; Lindae, Mary L.; Lowe, Nicholas J.

doi:10.1111/1523-1747.ep12264729

Cited by 16 publications

(6 citation statements)

References 3 publications

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“…The reasons for the differences between cultured cells and the rhino mouse are not understood at present. However, it is well known that potency and activity of a drug in vivo is affected by its absorption, distribution, and metabolism, as well as by its affinity for its receptor [21], Differences in the retention times of topi cally applied retinoids in hairless mouse skin have been described by Conner et al [22]. All-trans-retinoic acid and 13-cis-retinoic acid reside in the epidermis for a shorter time compared to etretinate and TTNPBethyl ester.…”

Section: Discussionmentioning

confidence: 99%

A Direct Comparison of Pharmacologic Effects of Retinoids on Skin Cells in vitro and in vivo

Varani

Gendimenico

Shah

et al. 1991

Skin Pharmacol Physiol

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The purpose of these studies was to directly compare the pharmacologic effects of retinoids on cutaneous cells in vitro and in vivo. Previously, it was demonstrated that all-trans-retinoic acid stimulates the proliferation of growth-arrested human keratinocytes and fíbroblasts in culture. In the present studies, all-trans-retinoic acid was compared to three other retinoids – 13-cis-retinoic acid, P-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napthalenyl-l-propenyl] benzoic acid (TTNPB) and M-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8,-tetramethyl-2-napthalenyl-l-propenyl] benzoic acid (meta-carboxy-TTNPB] – for growth stimulation using a cultured human squamous epithelial cell line (UM-SCC-1) and human dermal fíbroblasts. These four retinoids were also evaluated for their effects on reduction of horn-filled utriculi when topically applied to the skin of rhino mice. All-trans-retinoic acid stimulated proliferation of both fíbroblasts and epithelial cells over concentrations ranging from 0.01 to 1.0 μg/ml. In fíbroblasts, 13-cis-retinoic acid was less potent than all-trans-retinoic acid, whereas, in epithelial cells these two retinoids were equipotent. In contrast, TTNPB was more potent than all-trans-retinoic acid at stimulating the growth of both fíbroblasts and epithelial cells. The analog, meta-carboxy-TTNPB was essentially inactive as a growth stimulator of both cell types. In the rhino mouse utriculus reduction model, the rank order of potency for the retinoids was the same as that for in vitro cell growth stimulation (TTNPB > all-trans-retinoic acid > 13-cis-retinoic acid). Meta-carboxy-TTNPB was inactive at reducing utriculi at a dose of 5,000 times the ED₅₀ of TTNPB. In summary, the results of these studies show that the effects of retinoids on stimulating proliferation of fíbroblasts and epithelial cells correlate with their effects at reducing utriculi in the rhino mouse. Therefore, these in vitro models appear to have good relevance for studying the mechanisms of the pharmacologic effects of retinoids in vivo.

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Section: Discussionmentioning

confidence: 99%

A Direct Comparison of Pharmacologic Effects of Retinoids on Skin Cells in vitro and in vivo

Varani

Gendimenico

Shah

et al. 1991

Skin Pharmacol Physiol

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“…erties of the retinoid (Meeks et al, 1981), since inhibition of current was rapidly reversible with greater than 90% of the current being recovered immediately upon washing with RA-free solution. In contrast, RA remains in cell membranes for hours after washing (Connor et al, 1985), and during this time any general alterations in membrane architecture resulting from the lipophilic properties of RA should persist. We also showed that octanol blocks Ca currents in MHY206 cells, consistent with a recent report that this longchain alchohol blocks T-type Ca channels in guinea-pig inferior olivary cells (Llinas and Yarom, 1986).…”

Section: Discussionmentioning

confidence: 99%

Retinoic acid inhibits Ca²⁺ currents and cell proliferation in a B‐lymphocyte cell line

Bosma

Sidell²

1988

Journal Cellular Physiology

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Using the whole-cell variation of the patch-clamp technique, we have demonstrated that retinoic acid (RA) blocks Ca channels and inhibits cell proliferation in a mouse hybridoma cell line (MHY206) derived from a fusion of murine myeloma and splenic B cells. In 25 mM external Ca, and with an Na internal solution containing aspartate, cAMP, and Mg-ATP, inward currents were activated in these cells from holding potentials more negative than -70 mV, peaked at voltage steps up to -20 mV, and were voltage-inactivated within the 125-msec duration of the pulse. With more positive pulses, outward current carried by Na ions permeating through the Ca channels were seen. Application of RA blocked both inward and outward current through the Ca channels in a dose-dependent manner, with 50% block at a concentration of around 5 x 10(-5) M. Proliferation was blocked by 75% at that concentration, and the same relation between the reduction in current and proliferation was seen throughout the concentration range. A similar reduction of Ca currents and proliferation was demonstrated with octanol, a long-chain alcohol that has recently been reported to block Ca channels. These results suggest a role for Ca channels in the proliferation of MHY206 cells and implicate blockage of these channels as contributing to the antiproliferative activity of RA.

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“…Werner et al (1993) have shown that suprabasal expression of a dominant-negative FGF receptor mutant caused an increase in proliferation of basal keratinocytes. Retinoids applied topically to mouse skin were shown to rapidly reach epidermal and dermal cells (Connor et al 1985). However, it has not been made clear whether retinoids stimulate proliferation of basal keratinocytes directly via receptors within these cells or indirectly via those in suprabasal keratinocytes or dermal fibroblasts.…”

Section: Genes and Developmentmentioning

confidence: 99%

Suprabasal expression of a dominant-negative RXR alpha mutant in transgenic mouse epidermis impairs regulation of gene transcription and basal keratinocyte proliferation by RAR-selective retinoids.

Feng

Peng

et al. 1997

Genes Dev.

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To determine whether 9-cis retinoic acid receptors (RXRs) regulate the biological activity of all-trans retinoic acid (tRA) and its receptors (RARs) in skin, we have targeted a dominant-negative RXRot (dnRXRoL) lacking transactivation function AF-2 to differentiated suprabasal keratinocytes in the epidermis of transgenic mice. Driven by the suprabasal-specific keratin-10 gene promoter, expression of dnRXRa severely reduced the ability of RAR-selective ligands tRA and CD367 to induce epidermal mRNA levels of the CRABPII, CRBPI, and CRBPII genes, which contain RA-responsive elements (RAREs) DR1 and/or DR2. It also reduced gene-specific, synergistic induction of CRBPI mRNA by a combination of CD367 and RXR-selective SRl1237. Like endogenous RXR~, dnRXR~ in epidermal nuclear extracts from the transgenic mice competitively formed heterodimers with endogenous RARy on RAREs, suggesting that dnRXR~ impairs retinoid signaling by competing with endogenous RAR~,-RXRoL heterodimers. Histologically, the epidermis of dnRXR~ mice showed no detectable developmental abnormalities. Surprisingly, in adult animals, the suprabasal expression of dnRXRoL significantly reduced the ability of topically applied tRA to stimulate proliferation of undifferentiated keratinocytes in the basal layer of epidermis. RXR-selective ligands alone had no detectable effects on both normal and transgenic mouse epidermis. Accordingly, we suggest that in vivo: (1) in suprabasal keratinocytes, retinoids regulate gene transcription via RAR-RXR heterodimers in which RAR confers a predominant ligand response, whereas RXR AF-2 is required for liganded RAR AF-2 to efficiently trans-activate target genes, and (2) this suprabasal RXR-assisted mechanism indirectly regulates proliferation of basal keratinocytes likely via intercellular signaling.[Key Words: Retinoids; 9-cis retinoic acid receptor; transgenic mouse; epidermal keratinocytes; gene transcription; cell proliferation] Received September 4, 1996; revised version accepted November 11, 1996.Vitamin A (retinol) is an important regulator of epithelial cell homeostasis. All-trans retinoic acid (tRA) is the major biologically active metabolite of vitamin A. Clinically, tRA and related synthetic retinoids are widely used in the therapy of skin disorders such as cystic acne, psoriasis, photoaging skin, and certain epithelial malignancies (for review, see Peck and Di Giovanna 1994). These effects are thought to be mediated by members of two nuclear receptor gene families, retinoic acid receptor (RAR) genes and 9-cis retinoic acid (9cRA) receptor (RXR) genes. Each of the two families comprises three ZCorresponding author.

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Pharmacokinetics of Topically Applied Radiolabeled Retinoids in Hairless Mouse Epidermis and Dermis After Single Applications

Cited by 16 publications

References 3 publications

A Direct Comparison of Pharmacologic Effects of Retinoids on Skin Cells in vitro and in vivo

A Direct Comparison of Pharmacologic Effects of Retinoids on Skin Cells in vitro and in vivo

Retinoic acid inhibits Ca²⁺ currents and cell proliferation in a B‐lymphocyte cell line

Suprabasal expression of a dominant-negative RXR alpha mutant in transgenic mouse epidermis impairs regulation of gene transcription and basal keratinocyte proliferation by RAR-selective retinoids.

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Pharmacokinetics of Topically Applied Radiolabeled Retinoids in Hairless Mouse Epidermis and Dermis After Single Applications

Cited by 16 publications

References 3 publications

A Direct Comparison of Pharmacologic Effects of Retinoids on Skin Cells in vitro and in vivo

A Direct Comparison of Pharmacologic Effects of Retinoids on Skin Cells in vitro and in vivo

Retinoic acid inhibits Ca2+ currents and cell proliferation in a B‐lymphocyte cell line

Suprabasal expression of a dominant-negative RXR alpha mutant in transgenic mouse epidermis impairs regulation of gene transcription and basal keratinocyte proliferation by RAR-selective retinoids.

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Retinoic acid inhibits Ca²⁺ currents and cell proliferation in a B‐lymphocyte cell line