Binding of 9-cis-retinoic acid and all-trans-retinoic acid to retinoic acid receptors alpha, beta, and gamma. Retinoic acid receptor gamma binds all-trans-retinoic acid preferentially over 9-cis-retinoic acid

Allenby, Gary; Janocha, Reinhold; Kazmer, Sonja; Speck, J; Grippo, Joseph F.; Levin, Arthur A.

doi:10.1016/s0021-9258(19)89445-0

Cited by 100 publications

(10 citation statements)

References 38 publications

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“…Both atRA and 9cRA bind RAR with similarly high af®nity, if applied separately, whereas 9cRA preferentially transactivates RXR up to 40 times more ef®ciently than atRA (Heyman et al, 1992;Allenby et al, 1993). In human epidermis in vivo (Fisher et al, 1998) and in transfected COS cells in vitro (Allenby et al, 1994), however, RAR-g preferentially binds atRA over 9cRA when presented with mixtures of the two isomers. Furthermore, 9cRA and 13cRA applied topically on human skin were highly isomerized to atRA (Duell et al, 1996) and signi®cant isomerization of 9cRA to atRA was found in epidermal cells in vitro (Fisher et al, 1998).…”

Section: Discussionmentioning

confidence: 98%

13-cis Retinoic Acid Exerts its Specific Activity on Human Sebocytes through Selective Intracellular Isomerization to All-trans Retinoic Acid and Binding to Retinoid Acid Receptors

Tsukada

Schröder

Orfanos

et al. 2000

Journal of Investigative Dermatology

191

152

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Despite its potent biologic effect on human sebocytes, 13-cis retinoic acid exhibits low binding affinity for cellular retinoic acid binding proteins and nuclear retinoid receptors. Hence, 13-cis retinoic acid may represent a pro-drug possibly acting through all-trans isomerization. In this study, marked isomerization of 13-cis retinoic acid has been confirmed in cultured SZ95 sebocytes showing 2- to 15-fold higher levels of all-trans retinoic acid at 12-72 h, as measured by high performance liquid chromatography. In contrast, only low amounts of all-trans retinoic acid were converted intracellularly to its 13-cis isoform. 9-cis retinoic acid was not detected after either 13-cis retinoic acid or all-trans retinoic acid treatment. The rapid isomerization of 13-cis retinoic acid to high levels of all-trans retinoic acid was a sebocyte-specific event, as no significant isomerization of 13-cis retinoic acid to all-trans retinoic acid occurred in HaCaT keratinocytes. De novo mRNA expression of cytochrome P450 1A1, a major xenobiotic metabolizing enzyme, in SZ95 sebocytes was induced by all-trans retinoic acid, but not by 13-cis retinoic acid. In addition, mRNA levels of cellular retinoic acid-binding protein II, which is supposed to regulate the concentration of intracellular all-trans retinoic acid, rapidly increased under all-trans retinoic acid treatment (30 min-6 h), whereas the 13-cis retinoic acid effect was markedly weaker and delayed. Both 13-cis retinoic acid and all-trans retinoic acid suppressed mRNA expression of cytochrome P450 1A2. In parallel experiments, 13-cis retinoic acid significantly reduced SZ95 sebocyte proliferation at 10-7 M, show- ing 30-40% inhibition after 9 d. All-trans retinoic acid and 9-cis retinoic acid exhibited similar anti-proliferative effects. AGN 193109, a pan-antagonist of the retinoic acid receptors, antagonized the anti-proliferative activity of all retinoic acid isomers tested in a concentration-dependent manner with complete abolishment at ratios of 1:10 13-cis retinoic acid and 1:1 all-trans retinoic acid. Coincubation of SZ95 sebocytes with 13-cis retinoic acid and AGN 193109 did not alter the intracellular concentration of 13-cis retinoic acid and its isomerization profile. In contrast, the retinoid X receptor antagonist CD 3507 did not affect the inhibition of SZ95 sebocyte proliferation induced by retinoic acids. Our findings indicate: (i) a selective 13-cis retinoic acid isomerization to all-trans retinoic acid in the intracellular compartment of SZ95 sebocytes; (ii) a reduced all-trans retinoic acid inactivation process after 13-cis retinoic acid treatment as compared with treatment with all-trans retinoic acid; and (iii) a retinoic acid receptor-mediated inhibition of SZ95 sebocyte proliferation. These data explain the sebocyte-specific activity of 13-cis retinoic acid and support a pro-drug/drug relation between 13-cis retinoic acid and all-trans retinoic acid.

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Section: Discussionmentioning

confidence: 98%

13-cis Retinoic Acid Exerts its Specific Activity on Human Sebocytes through Selective Intracellular Isomerization to All-trans Retinoic Acid and Binding to Retinoid Acid Receptors

Tsukada

Schröder

Orfanos

et al. 2000

Journal of Investigative Dermatology

191

152

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“…1 and 2; Arnold et al, 2012). Of these retinoids, atRA activates retinoic acid receptors (RARs) and is believed to be the most important and biologically active endogenous RA isomer (Allenby et al, 1994;Chambon, 1996;Stevison et al, 2015). However, 13-cis-RA, 9-cis-RA, and 4-oxo-atRA can also activate RARs (Idres et al, 2002;Topletz et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

CYP26C1 Is a Hydroxylase of Multiple Active Retinoids and Interacts with Cellular Retinoic Acid Binding Proteins

et al. 2018

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The clearance of retinoic acid (RA) and its metabolites is believed to be regulated by the CYP26 enzymes, but the specific roles of CYP26A1, CYP26B1, and CYP26C1 in clearing active vitamin A metabolites have not been defined. The goal of this study was to establish the substrate specificity of CYP26C1, and determine whether CYP26C1 interacts with cellular retinoic acid binding proteins (CRABPs). CYP26C1 was found to effectively metabolize all- retinoic acid (RA), 9--retinoic acid (9--RA), 13--retinoic acid, and 4-oxo-RA with the highest intrinsic clearance toward 9--RA. In comparison with CYP26A1 and CYP26B1, CYP26C1 resulted in a different metabolite profile for retinoids, suggesting differences in the active-site structure of CYP26C1 compared with other CYP26s. Homology modeling of CYP26C1 suggested that this is attributable to the distinct binding orientation of retinoids within the CYP26C1 active site. In comparison with other CYP26 family members, CYP26C1 was up to 10-fold more efficient in clearing 4-oxo-RA (intrinsic clearance 153 l/min/pmol) than CYP26A1 and CYP26B1, suggesting that CYP26C1 may be important in clearing this active retinoid. In support of this, CRABPs delivered 4-oxo-RA and RA for metabolism by CYP26C1. Despite the tight binding of 4-oxo-RA and RA with CRABPs, the apparent Michaelis-Menten constant in biological matrix () value of these substrates with CYP26C1 was not increased when the substrates were bound with CRABPs, in contrast to what is predicted by free drug hypothesis. Together these findings suggest that CYP26C1 is a 4-oxo-RA hydroxylase and may be important in regulating the concentrations of this active retinoid in human tissues.

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“…The biological effects (except in vision) of retinoids are mediated by their interaction with the nuclear retinoic acid receptors (RARs) and retinoid X receptors. The known endogenous ligand for RARs is the acid derivative of all-trans-retinol (ROL), that is, all-trans-retinoic acid (RA), whereas its 9-cis isomer (9-cis-RA) activates both RARs and retinoid X receptors (Levin et al, 1992;Allenby et al, 1994). Blumberg et al (1996) and Achkar et al (1996) have challenged these views by providing some evidence that alltrans-4-oxo-retinaldehyde (oxoRAL) and all-trans-4-oxo-retinol (oxoROL) are capable of binding to and transactivating RARs.…”

Section: Introductionmentioning

confidence: 99%

Metabolism and Biological Activities of Topical 4-Oxoretinoids in Mouse Skin

Sorg

Tran

Carraux

et al. 2008

Journal of Investigative Dermatology

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Retinoic acid mediates most of the biological actions of vitamin A. It is oxidized by CYP26A1 to 4-oxoretinoic acid, considered as an inactive catabolite of retinoic acid. However, in the light of studies reporting the presence of 4-oxoretinal or 4-oxoretinol as the predominant retinoids during morphogenesis, we analyzed the retinoid-like biological activity of these oxoretinoids in mouse skin in vivo. Topical 4-oxoretinal and 4-oxoretinol promoted significant epidermal hyperplasia and metaplasia in mouse tail. They induced a moderate response for epidermal inflammation, compared with retinal, whereas neither 4-oxoretinal nor 4-oxoretinol prevented menadione-induced epidermal lipid peroxidation, unlike retinal and retinol. As analyzed by quantitative PCR, 4-oxoretinal and 4-oxoretinol did not reproduce the significant increased expression of genes coding for keratin 4, amphiregulin, heparin-EGF and CYP26A1, that did induce retinal and retinol. However, both retinal and 4-oxoretinal significantly inhibited the lipopolysaccharide-induced maturation of human dendritic cells in vitro. As analyzed in vivo and in vitro, 4-oxoretinal and 4-oxoretinol were not converted into retinoic acid. We conclude that 4-oxoretinal and 4-oxoretinol exert a moderate direct retinoid-like activity in vivo, thus confirming previous in vitro studies in amphibians showing 4-oxometabolites of vitamin A as bioactive agents rather than inactive catabolites.

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Binding of 9-cis-retinoic acid and all-trans-retinoic acid to retinoic acid receptors alpha, beta, and gamma. Retinoic acid receptor gamma binds all-trans-retinoic acid preferentially over 9-cis-retinoic acid

Cited by 100 publications

References 38 publications

13-cis Retinoic Acid Exerts its Specific Activity on Human Sebocytes through Selective Intracellular Isomerization to All-trans Retinoic Acid and Binding to Retinoid Acid Receptors

13-cis Retinoic Acid Exerts its Specific Activity on Human Sebocytes through Selective Intracellular Isomerization to All-trans Retinoic Acid and Binding to Retinoid Acid Receptors

CYP26C1 Is a Hydroxylase of Multiple Active Retinoids and Interacts with Cellular Retinoic Acid Binding Proteins

Metabolism and Biological Activities of Topical 4-Oxoretinoids in Mouse Skin

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