Cloning of monkey RALDH1 and characterization of retinoid metabolism in monkey kidney proximal tubule cells

All-trans and 9-cis retinoic acids function as ligands for retinoic acid receptors (RARs and RXRs), which are ligand-dependent transcription factors and play important roles in development and cellular differentiation. Several retinal dehydrogenases are likely to contribute to the production of all-trans and 9-cis RAs in vivo, but their respective roles in different tissues are still poorly characterized. We have previously characterized and cloned from kidney tissues the rat retinal dehydrogenase type 1 (RALDH1), which oxidizes all-trans and 9-cis retinal with high efficiency but is inactive with 13-cis retinal. Here we have characterized the retinal-oxidizing activity in monkey JTC12 cells, which are derived from kidney proximal tubules. In vitro assay of cell lysates revealed the presence of a NAD+-dependent dehydrogenase that catalyzed the oxidation of all-trans, 9-cis, and 13-cis retinal. Northern blot analysis of JTC12 RNAs and cloning by reverse transcription-polymerase chain reaction demonstrated expression of a monkey homolog of RALDH1. Bacterially expressed JTC12 RALDH1 catalyzed conversion of all three retinal isomers, with a higher catalytic efficiency for 9-cis retinal than for all-trans and 13-cis retinal. Accordingly, live JTC12 produced 9-cis retinoic acid more efficiently than all-trans retinoic acid from their respective retinal precursors.Only metabolites corresponding to the same steric conformation were formed from 9-cis or all-trans retinal, indicating a lack of detectable isomerizing activity in JTC12 cells. All-trans and 9-cis retinoic acids function as ligands for retinoic acid receptors (RARs and RXRs), which are ligand-dependent transcription factors and play important roles in development and cellular differentiation. Several retinal dehydrogenases are likely to contribute to the production of all-trans and 9-cis RAs in vivo, but their respective roles in different tissues are still poorly characterized. We have previously characterized and cloned from kidney tissues the rat retinal dehydrogenase type 1 (RALDH1), which oxidizes all-trans and 9-cis retinal with high efficiency but is inactive with 13-cis retinal. Here we have characterized the retinal-oxidizing activity in monkey JTC12 cells, which are derived from kidney proximal tubules. In vitro assay of cell lysates revealed the presence of a NAD+-dependent dehydrogenase that catalyzed the oxidation of all-trans, 9-cis, and 13-cis retinal. Northern blot analysis of JTC12 RNAs and cloning by reverse transcription-polymerase chain reaction demonstrated expression of a monkey homolog of RALDH1. Bacterially expressed JTC12 RALDH1 catalyzed conversion of all three retinal isomers, with a higher catalytic efficiency for 9-cis retinal than for all-trans and 13-cis retinal. Accordingly, live JTC12 produced 9-cis retinoic acid more efficiently than all-trans retinoic acid from their respective retinal precursors. Only metabolites corresponding to the same steric conformation were formed from 9-cis or all-trans retinal, indicating a lack of detectable isomerizing activity in JTC12 cells. Retinoids are important regulators of cell growth, differentiation, and embryonic development (1Strickland S. Sawey M.J. Studies on the effect of retinoids on the differentiation of teratocarcinoma stem cells in vitro and in vivo.Dev. Biol. 1980; 78: 76-85Google Scholar, 2Gudas L.J. Sporn M.B. Roberts A.B. Cellular biology and chemistry of the retinoids.in: Sporn M.B. Roberts A.B. Goodman D.S. The Retinoids: Biology, Chemistry, and Medicine. Raven Press Ltd, New York1994: 443-520Google Scholar, 3Hofmann C. Eichele G. Retinoids in development.in: Sporn M.B. Roberts A.B. Goodman D.S. The Retinoids: Biology, Chemistry, and Medicine. Raven Press Ltd, New York1994: 319-350Google Scholar). They are also needed for normal vision, reproduction, and immunity (4Saari J.C. Retinoids in photosensitive systems.in: Sporn M.B. Roberts A.B. Goodman D.S. The Retinoids: Biology, Chemistry, and Medicine. Raven Press Ltd, New York1994: 351-386Google Scholar, 5Armstrong R.B. Ashenfelter K.O. Eckhoff C. Levin A.A. Shapiro S.S. General and reproductive toxicology of retinoids.in: Sporn M.B. Roberts A.B. Goodman D.S. The Retinoids: Biology, Chemistry, and Medicine. Raven Press Ltd, New York1994: 545-572Google Scholar, 6Ross A.C. Hammerling U. Retinoids and the immune system.in: Sporn M.B. Roberts A.B. Goodman D.S. The Retinoids: Biology, Chemistry, and Medicine. Raven Press Ltd, New York1994: 521-544Google Scholar). The biological actions of retinoids are mediated through binding and modulation of retinoic acid receptors (RARs) or retinoid X receptors (RXRs), which function as ligand-dependent transcription factors (7Chambon P. A decade of molecular biology of retinoic acid receptors.FASEB J. 1995; 10: 940-954Google Scholar). All-trans retinoic acid (RA) is a natural ligand for RARs, and 9-cis RA binds to both RARs and RXRs (8Mangelsdorf D.J. Umesono K. Evans R.M. The retinoid receptors.in: Sporn M.B. Roberts A.B. Goodman D.S. The Retinoids: Biology, Chemistry, and Medicine. Raven Press Ltd, New York1994: 319-349Google Scholar). The influence of vitamin A (retinol) in the control of gene expression is made possible by enzymes regulating RA synthesis. RA is formed from retinol via a 2-step metabolic pathway that involves oxidation of retinol to retinal and then of retinal to RA (9Duester G. Families of retinoid dehydrogenases regulating vitamin A function: production of visual pigment and retinoic acid.Eur. J. Biochem. 2000; 267: 4315-4324Google Scholar, 10Napoli J.L. Retinoic acid: its biosynthesis and metabolism.Prog. Nucleic Acid Res. 2000; 63: 139-188Google Scholar). Although the metabolic pathways leading to the formation of all-trans and 9-cis RAs are beginning to be elucidated, the enzymes controlling production of these compounds within specific cells and tissues are still poorly characterized. In particular, it is not firmly established whether both all-trans and 9-cis RAs can be produced from the precursor all-trans retinol. Several studies have shown that externally supplied all-trans, 9-cis, and 13-cis RAs are isomerized into cis or trans RAs in cells and tissues and appear to reach equilibrium (11Sundaresan P.R. Bhat P.V. Ion-pair high-pressure liquid chromatography of cis-trans isomers of retinoic acid in tissues of vitamin A sufficient rats.J. Lipid Res. 1982; 23: 448-455Google Scholar, 12Cullum M.E. Zile M.H. Metabolism of all-trans retinoic acid and all-trans retinyl acetate: demonstration of common physiological metabolites in rat small intestinal mucosa and circulation.J. Biol. Chem. 1985; 260: 10590-10596Google Scholar, 13Bhat P.V. Jetten A.M. Metabolism of all-trans retinol and all-trans retinoic acid in rabbit tracheal epithelial cells in culture.Biochim. Biophys. Acta. 1987; 922: 18-27Google Scholar, 14Kojima R. Fujimore T. Kiyota N. Toriya Y. Fukuda T. Ohashi T. Sato T. Yoshizawa Y. Takeyama K.I. Mano H. Masushige S. Kato S. In vivo isomerization of retinoic acids: rapid isomer exchange and gene expression.J. Biol. Chem. 1994; 269: 32700-32707Google Scholar, 15Urbach J. Rando R.R. Isomerization of all-trans retinoic acid to 9-cis retinoic acid.Biochem. J. 1994; 299: 459-465Google Scholar, 16Disdier B. Marchetti M.N. Bun H. Placidi M. Durand A. Kinetics of plasma and tissue distribution of 9-cis retinoic acid in rats.Skin Pharmacol. Appl. Skin Physiol. 2000; 13: 9-16Google Scholar). Since no isomerase(s) involved in these processes have been identified, it is generally believed that the interconversion of cis-trans RA occurs in cells through nonenzymatic mechanism(s), although it is not clear whether this can happen at the level of retinol, retinal, and/or retinoic acid (16Disdier B. Marchetti M.N. Bun H. Placidi M. Durand A. Kinetics of plasma and tissue distribution of 9-cis retinoic acid in rats.Skin Pharmacol. Appl. Skin Physiol. 2000; 13: 9-16Google Scholar, 17Blaner W.S. Cellular metabolism and actions of 13-cis retinoic acid.J. Am. Acad. Dermatol. 2001; 45: S129-S135Google Scholar). We have previously reported the purification, cloning, and characterization of a retinal dehydrogenase type 1 (RALDH1) from rat kidney that oxidized all-trans and 9-cis retinal, but not 13-cis retinal to the corresponding acids (18Labrecque J. Bhat P.V. Lacroix A. Purification and partial characterization of a rat kidney aldehyde dehydrogenase that oxidizes retinal to retinoic acid.Biochem. Cell Biol. 1993; 71: 85-89Google Scholar, 19Labrecque J. Dumas F. Lacroix A. Bhat P.V. A novel isozyme of aldehyde dehydrogenase involved in the biosynthesis of 9-cis and all-trans retinoic acid.Biochem. J. 1995; Scholar, P.V. J. Lacroix A. A. of a rat aldehyde dehydrogenase with high activity for retinal 1995; Scholar). We have also demonstrated that rat RALDH1 is expressed in the proximal of the a in RA production P.V. M. Y. S. of retinal dehydrogenase expression development in the Scholar). In rat RALDH1 is expressed in tissues as and indicating its in RA production needed for epithelial cell differentiation P.V. dehydrogenase gene expression in and small of development and in vitamin A Scholar, A. M. Bhat P.V. of retinal dehydrogenase type 1 in the and Res. 2000; Scholar). In RALDH1 is expressed in kidney and tissues R. Metabolism of and in of and Biol. Chem. Scholar). the in the RALDH1 is in of but is not expressed in the kidney H. G. for and in the control of ligand production for embryonic retinoid Scholar). In the we have characterized the expressed in a monkey kidney cell and the production of isomers of RA by these cells. The cloned to be the to RALDH1. expression in kidney JTC12 cells is with the reported high expression of rat RALDH1 in In monkey catalyzed formation of all-trans, 9-cis, or 13-cis isomers of RA from the corresponding retinal isomers in with a higher catalytic efficiency for 9-cis retinal. 9-cis RA formed more efficiently than all-trans RA JTC12 cells were with all-trans or 9-cis retinal, detectable equilibrium RA 9-cis, and 13-cis retinal, and all-trans and 13-cis RAs were from all-trans, 9-cis, and 13-cis retinol were from corresponding retinal by as P.V. Lacroix A. of on the of isomers of retinol in liquid 260: Scholar). 9-cis RA from The of the retinal by reverse and normal high-pressure liquid chromatography P.V. P.R. liquid chromatography of vitamin A Chem. and to be at were from the JTC12 kidney proximal cells were in with high and and at in of in JTC12 cells by Northern blot as P.V. dehydrogenase gene expression in and small of development and in vitamin A Scholar). RNAs from cells were with to the to of were in and to a The were and at They were then with at for and then with at for the were with at for rat kidney that with as a cells and tissues were in of and a of The at to and The in the in by and to were with in with in rat RALDH1 corresponding to S. and aldehyde dehydrogenases are that function as 2000; supplied by in RALDH1 cloned from JTC12 by reverse transcription-polymerase chain reaction The from RALDH1 were in R. aldehyde dehydrogenase 1 Scholar). The and reverse of the and and and the reverse of with of from JTC12 cells reverse and by a that both and and The on and a on The that the into the and of the expression from were The RALDH1 in into and expressed with at the The expressed from with a by with as previously G. Bhat P.V. analysis of retinal dehydrogenase for retinal Biophys. Acta. Scholar). The of the by for monkey RALDH1 activity were as previously for rat kidney RALDH1 P.V. Lacroix A. of retinal-oxidizing activity in rat Biophys. Acta. Scholar). Cell lysates or tissue were for at with assay of all-trans, 9-cis, or 13-cis retinal in and in and the of of retinal were with a of the the assay with of and the reaction by were or in to the of at were in retinoid metabolism In and cells in were with 1 or all-trans retinal for In cells were for with all-trans, 9-cis, or 13-cis retinal. Retinoids were in and their by and their to the cells for control with with the and the cells were with They were then from the by and in Cell lysates were by and three for a the were at for at to cell and were retinol, and RA were from the cell lysates with for the and of the formation of retinyl the lysates were with of were by chromatography as P.V. S. metabolism in conversion of retinol to Lipid Res. and their were by and P.V. high-pressure liquid of and Biochem. 1980; Scholar). retinol, and retinal were on a from with as the and at a of In this are not from but are from their respective The of isomer and and the formation of retinyl were in P.V. high-pressure liquid of and Biochem. 1980; Scholar, P.V. Lacroix A. of isomers of retinol and retinoic acid in liquid F. in Scholar). Retinoids were by at on a liquid chromatography were and by their and the of of Northern blot analysis of from JTC12 cells rat kidney RALDH1 as a revealed The of the higher than that of rat kidney RALDH1 the with rat RALDH1 but not with the from JTC12 cells, in the blot analysis RALDH1 no not indicating that the of JTC12 from that of rat RALDH1 acids the by the that this not to in this We whether the JTC12 with as and which also retinal oxidation G. Bhat P.V. analysis of retinal dehydrogenase for retinal Biophys. Acta. Scholar, F. Y. S. T. Umesono K. dehydrogenase a dehydrogenase expressed in Biol. Chem. 2000; Scholar). A corresponding to not and a a not that the in JTC12 cells is the monkey homolog of the RALDH1. whether the JTC12 activity with retinal we retinal dehydrogenase in cell all-trans retinal as to rat kidney the JTC12 cell high activity The of JTC12 cell to the oxidation of all-trans, 9-cis, and 13-cis retinal to the of the expressed in these cells with reported for or rat RALDH1. all three enzymes oxidation of all-trans and 9-cis retinal, in their with 13-cis retinal, which is a for RALDH1. The of RA production JTC12 cell were to to The in these high activity with 9-cis retinal, and activity with all-trans and 13-cis retinal the of the JTC12 with 13-cis retinal is to that of the than to of the the of the and of the that the expressed in JTC12 cells is to RALDH1 J. Dumas F. Lacroix A. Bhat P.V. A novel isozyme of aldehyde dehydrogenase involved in the biosynthesis of 9-cis and all-trans retinoic acid.Biochem. J. 1995; Scholar, P.V. H. of the aldehyde dehydrogenase for retinal Pharmacol. Scholar). Since the characterization of the JTC12 high with we derived from in a assay to the corresponding to the monkey The a of acids acid with R. aldehyde dehydrogenase 1 Scholar). RALDH1 also and acid with rat and that acids of monkey RALDH1 and rat RALDH1 in the by the in its lack of with JTC12 of acid of monkey RALDH1 with is by and and were from and whether the cloned a with for retinal oxidation to with we expressed it in The molecular of The of the expressed for all-trans retinal oxidation to the of the characterized in we the activity of for retinal isomer to the activity in cell the also catalyzed oxidation of the three retinal isomer to the respective RAs not for all-trans RA is for and monkey RALDH1. and of and were in the The reaction with of all-trans retinal. is the of whether the of JTC12 for retinal are to of P.V. H. of the aldehyde dehydrogenase for retinal Pharmacol. we its with all-trans, 9-cis, and 13-cis retinal. The the activity for 9-cis retinal by all-trans and 13-cis retinal oxidation The for 13-cis retinal than for all-trans retinal. no in the catalytic efficiency of 13-cis and all-trans retinal conversion to the respective RAs the 9-cis retinal higher catalytic efficiency with all-trans retinal the were to of P.V. H. of the aldehyde dehydrogenase for retinal Pharmacol. of of JTC12 cells for retinal for from JTC12 cells and expressed in The as in and The the of or more in the of is the of three in a for from JTC12 cells and expressed in The as in and The the of or more in the of is the of three The presence of of retinal, the in the of RA from retinol, been demonstrated in tissues Zile M. M. chromatography of vitamin A compounds in biological formation of retinoic acid from retinyl Lipid Res. Scholar). is whether is in cells RA Since JTC12 cells high of that is of all-trans, 9-cis, and 13-cis retinal, metabolic studies with these cells as to the of conversion retinal In JTC12 cells were for with of all-trans retinal to the of the assay for of RA and the of the retinal Cell by and that the retinal were not Since a in RA in this of more metabolic studies were then in JTC12 cells of retinal The of all-trans, 9-cis, and 13-cis retinal to be than by analysis were in the The of the from cells with all-trans, 9-cis, or 13-cis retinal for are in and The cells all-trans retinal from the and it into all-trans retinol or all-trans RA and no cis isomers of retinol or RA were we not retinal in cell of its of with 9-cis retinal in the formation of 9-cis RA by the cells and all-trans RA all-trans retinal were that 9-cis retinol not In cells with for 1 not metabolites of all-trans or 9-cis retinal, indicating that metabolites were formed in the cells. the the metabolic of 13-cis retinal formation of all-trans all-trans retinol, and all-trans retinal with no 13-cis RA or 13-cis retinol of 13-cis retinal were still in the cells Since all-trans retinoid metabolites were in cells with 13-cis retinal, is that of the 13-cis retinal have been isomerized in the to all-trans retinal, and that all-trans retinal have been by the cells and to the respective RA or retinol. this we cells with 13-cis retinal and the retinoids from the more than of 13-cis retinal isomerized to all-trans retinal in the at of not we have not in the of the steric of 13-cis retinal in the of the metabolism of 13-cis retinal in of retinal isomers and their metabolites in JTC12 cells and the as as the of the all-trans 9-cis and 13-cis retinal that were in the metabolic the metabolic of cells with all-trans, 9-cis, and 13-cis retinal for 1 the of 9-cis and 13-cis all-trans 9-cis and 13-cis and all-trans Although the presence of retinyl not of the to to and the isomers of retinyl chromatography and analysis demonstrated the presence of retinyl in cells with all three retinal isomers not indicating that JTC12 cells retinyl and retinol in the of retinyl The of all-trans or 9-cis RA or retinol formed in cells for with all-trans or 9-cis retinal, is in of the cellular of 9-cis RA were higher than of all-trans all-trans retinol more than 9-cis retinol the same higher efficiency in the conversion of 9-cis retinal to RA than of the all-trans isomer is with the in vitro of the monkey RALDH1. Although a of is on the of retinoid receptors in retinoid is the metabolic pathways involved in the biosynthesis of RA isomers in the pathways of retinoid isomers in cell we characterized the RA expressed in a cell The expression and activity for the three retinal isomers of the expressed in JTC12 cells that JTC12 is a to the biosynthesis of RA isomers in a cellular We have previously reported the of for retinal isomer J. Dumas F. Lacroix A. Bhat P.V. A novel isozyme of aldehyde dehydrogenase involved in the biosynthesis of 9-cis and all-trans retinoic acid.Biochem. J. 1995; Scholar, G. Bhat P.V. analysis of retinal dehydrogenase for retinal Biophys. Acta. Scholar, P.V. H. of the aldehyde dehydrogenase for retinal Pharmacol. and characterized the acid that are important for all-trans and 9-cis retinal oxidation N. J. C. Bhat P.V. S. aldehyde dehydrogenases specific for all-trans or 9-cis Biol. Chem. Scholar). The that the JTC12 activity catalyzed the oxidation of the three retinal isomer and the lack of with a for which also oxidizes the three retinal isomers G. Bhat P.V. analysis of retinal dehydrogenase for retinal Biophys. Acta. that this activity is to P.V. H. of the aldehyde dehydrogenase for retinal Pharmacol. Scholar). by of the cloned and the of the as molecular and were to be to of P.V. H. of the aldehyde dehydrogenase for retinal Pharmacol. Scholar). the that with rat kidney RALDH1 at with the cloned not that the cloned monkey RALDH1 is the retinal dehydrogenase expressed to high in JTC12 cells. of retinoid that is not clear is the metabolic of all-trans, 9-cis, and 13-cis RA formation in is generally that all-trans retinol is the precursor retinoid for the formation of RAs in vivo J. S. R. A. W.S. K. biosynthesis of 9-cis retinoic 2000; Scholar). in it is generally believed that all-trans and 13-cis RA are retinoid W.S. Cellular metabolism and actions of 13-cis retinoic acid.J. Am. Acad. Dermatol. 2001; 45: S129-S135Google Scholar, N. J. C. Bhat P.V. S. aldehyde dehydrogenases specific for all-trans or 9-cis Biol. Chem. the of 9-cis RA in tissues and cells is still (8Mangelsdorf D.J. Umesono K. Evans R.M. The retinoid receptors.in: Sporn M.B. Roberts A.B. Goodman D.S. The Retinoids: Biology, Chemistry, and Medicine. Raven Press Ltd, New York1994: 319-349Google Scholar, Metabolism of a physiological of in vitamin Biochem. Biophys. 2001; Scholar, R. of retinoic acid in the embryonic 2001; Scholar, R. of binding and receptors development in important of retinal dehydrogenase type in of Biol. 2000; Scholar, C. M. distribution of retinoids normal development and in 1995; Scholar). the of 9-cis and 13-cis retinol been J. Dumas F. Lacroix A. Bhat P.V. A novel isozyme of aldehyde dehydrogenase involved in the biosynthesis of 9-cis and all-trans retinoic acid.Biochem. J. 1995; Scholar, J. S. R. A. W.S. K. biosynthesis of 9-cis retinoic 2000; Scholar). Several enzymes involved in the oxidation of the RA pathway have been shown to the oxidation of all-trans, 9-cis, and 13-cis retinol to the respective (9Duester G. Families of retinoid dehydrogenases regulating vitamin A function: production of visual pigment and retinoic acid.Eur. J. Biochem. 2000; 267: 4315-4324Google Scholar, 10Napoli J.L. Retinoic acid: its biosynthesis and metabolism.Prog. Nucleic Acid Res. 2000; 63: 139-188Google Scholar, R. S. D.J. W.S. and characterization of a that 9-cis retinol Biol. Chem. Scholar). In the of RA retinal is oxidized by at three of NAD+-dependent in tissue expression and catalytic for retinal isomers (9Duester G. Families of retinoid dehydrogenases regulating vitamin A function: production of visual pigment and retinoic acid.Eur. J. Biochem. 2000; 267: 4315-4324Google Scholar). have demonstrated that the retinoids their steric the oxidation of retinol to RA in vitro or enzymes J. Dumas F. Lacroix A. Bhat P.V. A novel isozyme of aldehyde dehydrogenase involved in the biosynthesis of 9-cis and all-trans retinoic acid.Biochem. J. 1995; Scholar, G. Bhat P.V. analysis of retinal dehydrogenase for retinal Biophys. Acta. Scholar, J. S. R. A. W.S. K. biosynthesis of 9-cis retinoic 2000; Scholar). the metabolism of retinoids within tissues and cells is by the cells metabolic that to retinyl to and to acid (9Duester G. Families of retinoid dehydrogenases regulating vitamin A function: production of visual pigment and retinoic acid.Eur. J. Biochem. 2000; 267: 4315-4324Google Scholar, 10Napoli J.L. Retinoic acid: its biosynthesis and metabolism.Prog. Nucleic Acid Res. 2000; 63: 139-188Google Scholar, W.S. and retinoic acid Sporn M.B. Roberts A.B. Goodman D.S. The Retinoids: Biology, Chemistry, and Medicine. Raven Press Ltd, New York1994: Scholar). Since JTC12 cells high of activity that oxidation of all three retinal isomers into the corresponding RA isomers in we to the metabolites formed from of retinal and to whether isomerization can in live JTC12 cells. analysis of cell with retinal isomers a production of RA produced in JTC12 cells Although retinal can with of and acids J. of visual pigment of the in no at the In to oxidation to all-trans retinal also to retinol and not the presence of retinol and in JTC12 cells. Since the metabolic conversion of retinol to RA is a the a retinol dehydrogenase J.L. Retinoic acid: its biosynthesis and metabolism.Prog. Nucleic Acid Res. 2000; 63: 139-188Google Scholar). Several have reported that to retinol and to retinyl are the metabolic of retinal isomers in cells and tissues J. S. R. A. W.S. K. biosynthesis of 9-cis retinoic 2000; Scholar, G. H. Metabolism of isomers in 13-cis and but not 9-cis of retinoid Scholar). no retinol a with 9-cis retinal, high of 9-cis RA were produced with all-trans RA with the with RALDH1 in vitro is that all-trans 9-cis retinal detectable in the cells indicating rapid of the by and In vivo, retinal is formed from the oxidation of retinol or of the of retinal from is to retinol and then to retinyl which are in cells, or in the of intestinal are by to the and in cells The biosynthesis and metabolism of and retinol Lipid Res. Scholar). The of of 9-cis and 13-cis are than that of the all-trans isomer A. formation of 9-cis, and all-trans from isomers of J. 1994; Scholar). the of conversion of retinal isomers, formed from to retinol or In the expression and the of and influence the metabolism of retinal on retinal metabolism by JTC12 cells the that the of RA or retinol from retinal on the and of and retinal for retinal Since retinal not in in the cells, it is likely that retinal by the cells is to RA or retinol. A demonstrated that all-trans RA is a of 13-cis retinal in with 13-cis retinal G. H. Metabolism of isomers in 13-cis and but not 9-cis of retinoid Scholar). We also production of all-trans metabolites in JTC12 cells with 13-cis retinal, but this isomerization be to the conversion of 13-cis retinal to all-trans retinal in whether 13-cis retinal its steric metabolic conversion in the cells to it this not with all-trans or 9-cis retinal, which were to their respective metabolites detectable isomerization by live JTC12 cells Several studies have shown that isomerization of the trans and cis isomers of externally RAs and of RA in cells, and (11Sundaresan P.R. Bhat P.V. Ion-pair high-pressure liquid chromatography of cis-trans isomers of retinoic acid in tissues of vitamin A sufficient rats.J. Lipid Res. 1982; 23: 448-455Google Scholar, 12Cullum M.E. Zile M.H. Metabolism of all-trans retinoic acid and all-trans retinyl acetate: demonstration of common physiological metabolites in rat small intestinal mucosa and circulation.J. Biol. Chem. 1985; 260: 10590-10596Google Scholar, 13Bhat P.V. Jetten A.M. Metabolism of all-trans retinol and all-trans retinoic acid in rabbit tracheal epithelial cells in culture.Biochim. Biophys. Acta. 1987; 922: 18-27Google Scholar, 14Kojima R. Fujimore T. Kiyota N. Toriya Y. Fukuda T. Ohashi T. Sato T. Yoshizawa Y. Takeyama K.I. Mano H. Masushige S. Kato S. In vivo isomerization of retinoic acids: rapid isomer exchange and gene expression.J. Biol. Chem. 1994; 269: 32700-32707Google Scholar, 15Urbach J. Rando R.R. Isomerization of all-trans retinoic acid to 9-cis retinoic acid.Biochem. J. 1994; 299: 459-465Google Scholar). that the of RAs in is 1 which of the all-trans RA and of the 9-cis RA produced in assay of JTC12 cell in vivo conversion of 9-cis to all-trans RA in JTC12 cells, it occurs with are with the of G. H. Metabolism of isomers in 13-cis and but not 9-cis of retinoid and J.C. a for the of embryonic retinoid metabolism of all-trans and to their corresponding acid 1995; 23: reported that all-trans and 9-cis RA are the in vivo metabolites of all-trans and 9-cis retinal, P. C. H. G. H. H. and function of and acid in Biophys. Res. demonstrated that cells not all-trans RA to 9-cis but 9-cis RA from all-trans retinol. these that RA isomers are in cells from different precursor retinoids than by studies the and of retinal enzymes N. J. C. Bhat P.V. S. aldehyde dehydrogenases specific for all-trans or 9-cis Biol. Chem. in in vitro as as in in into the formation and metabolic conversion of by a from the of to and The for and M. for aldehyde dehydrogenase high-pressure liquid chromatography retinoic acid and retinal dehydrogenase type retinoic acid retinoid X reverse transcription-polymerase chain reaction

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