Publications

• Identification and characterization of a stereospecific human enzyme that catalyzes 9-cis-retinol oxidation. A possible role in 9-cis-retinoic acid formation.

  Mertz J.R., Shang E., Piantedosi R., Wei S., Wolgemuth D.J., Blaner W.S.

  All-trans- and 9-cis-retinoic acid are active retinoids for regulating expression of retinoid responsive genes, serving as ligands for two classes of ligand-dependent transcription factors, the retinoic acid receptors and retinoid X receptors. Little is known, however, regarding 9-cis-retinoic aci ... >> More

  All-trans- and 9-cis-retinoic acid are active retinoids for regulating expression of retinoid responsive genes, serving as ligands for two classes of ligand-dependent transcription factors, the retinoic acid receptors and retinoid X receptors. Little is known, however, regarding 9-cis-retinoic acid formation. We have obtained a 1.4-kilobase cDNA clone from a normalized human breast tissue library, which when expressed in CHO cells encodes a protein that avidly catalyzes oxidation of 9-cis-retinol to 9-cis-retinaldehyde. This protein also catalyzes oxidation of 13-cis-retinol at a rate approximately 10% of that of the 9-cis isomer but does not catalyze all-trans-retinol oxidation. NAD+ was the preferred electron acceptor for oxidation of 9-cis-retinol, although NADP+ supported low rates of 9-cis-retinol oxidation. The rate of 9-cis-retinol oxidation was optimal at pHs between 7.5 and 8. Sequence analysis indicates that the cDNA encodes a protein of 319 amino acids that resembles members of the short chain alcohol dehydrogenase protein family. mRNA for the protein is most abundant in human mammary tissue followed by kidney and testis, with lower levels of expression in liver, adrenals, lung, pancreas, and skeletal muscle. We propose that this cDNA encodes a previously unknown stereospecific enzyme, 9-cis-retinol dehydrogenase, which probably plays a role in 9-cis-retinoic acid formation. << Less

  J. Biol. Chem. 272:11744-11749(1997) [PubMed] [EuropePMC]

  This publication is cited by 2 other entries.

• cDNA cloning and characterization of a cis-retinol/3alpha-hydroxysterol short-chain dehydrogenase.

  Chai X., Zhai Y., Napoli J.L.

  We report a mouse cDNA that encodes a 317-amino acid short-chain dehydrogenase which recognizes as substrates 9-cis-retinol, 11-cis-retinol, 5alpha-androstan-3alpha,17beta-diol, and 5alpha-androstan-3alpha-ol-17-one. This cis-retinol/androgen dehydrogenase (CRAD) shares closest amino acid similari ... >> More

  We report a mouse cDNA that encodes a 317-amino acid short-chain dehydrogenase which recognizes as substrates 9-cis-retinol, 11-cis-retinol, 5alpha-androstan-3alpha,17beta-diol, and 5alpha-androstan-3alpha-ol-17-one. This cis-retinol/androgen dehydrogenase (CRAD) shares closest amino acid similarity with mouse retinol dehydrogenase isozymes types 1 and 2 (86 and 91%, respectively). Recombinant CRAD uses NAD+ as its preferred cofactor and exhibits cooperative kinetics for cis-retinoids, but Michaelis-Menten kinetics for 3alpha-hydroxysterols. Unlike recombinant retinol dehydrogenase isozymes, recombinant CRAD was inhibited by 4-methylpyrazole, was not stimulated by ethanol, and did not require phosphatidylcholine for optimal activity. CRAD mRNA was expressed intensely in kidney and liver, in contrast to retinol dehydrogenase isozymes, which show strong mRNA expression only in liver. CRAD mRNA expression was widespread (relative abundance): kidney (100) > liver (92) > small intestine (9) = heart (9) > retinal pigment epithelium and sclera (4.5) > brain (2) > retina and vitreous (1.6) > spleen (0.7) > testis (0.6) > lung (0.4). CRAD may catalyze the first step in an enzymatic pathway from 9-cis-retinol to generate the retinoid X receptor ligand 9-cis-retinoic acid and/or may regenerate dihydrotestosterone from its catabolite 5alpha-androstan-3alpha,17beta-diol. These data also illustrate the multifunctional nature of short-chain dehydrogenases and provide a potential mechanism for androgen-retinoid interactions. << Less

  J. Biol. Chem. 272:33125-33131(1997) [PubMed] [EuropePMC]

  This publication is cited by 3 other entries.

• Absolute Reliability and Concurrent Validity of Hand Held Dynamometry and Isokinetic Dynamometry in the Hip, Knee and Ankle Joint: Systematic Review and Meta-analysis.

  Chamorro C., Armijo-Olivo S., De la Fuente C., Fuentes J., Javier Chirosa L.

  The purpose of the study is to establish absolute reliability and concurrent validity between hand-held dynamometers (HHDs) and isokinetic dynamometers (IDs) in lower extremity peak torque assessment. Medline, Embase, CINAHL databases were searched for studies related to psychometric properties in ... >> More

  The purpose of the study is to establish absolute reliability and concurrent validity between hand-held dynamometers (HHDs) and isokinetic dynamometers (IDs) in lower extremity peak torque assessment. Medline, Embase, CINAHL databases were searched for studies related to psychometric properties in muscle dynamometry. Studies considering standard error of measurement SEM (%) or limit of agreement LOA (%) expressed as percentage of the mean, were considered to establish absolute reliability while studies using intra-class correlation coefficient (ICC) were considered to establish concurrent validity between dynamometers. In total, 17 studies were included in the meta-analysis. The COSMIN checklist classified them between fair and poor. Using HHDs, knee extension LOA (%) was 33.59%, 95% confidence interval (CI) 23.91 to 43.26 and ankle plantar flexion LOA (%) was 48.87%, CI 35.19 to 62.56. Using IDs, hip adduction and extension; knee flexion and extension; and ankle dorsiflexion showed LOA (%) under 15%. Lower hip, knee, and ankle LOA (%) were obtained using an ID compared to HHD. ICC between devices ranged between 0.62, CI (0.37 to 0.87) for ankle dorsiflexion to 0.94, IC (0.91to 0.98) for hip adduction. Very high correlation were found for hip adductors and hip flexors and moderate correlations for knee flexors/extensors and ankle plantar/dorsiflexors. << Less

  Open Med (Wars) 12:359-375(2017) [PubMed] [EuropePMC]

• Activity of human 11-cis-retinol dehydrogenase (Rdh5) with steroids and retinoids and expression of its mRNA in extra-ocular human tissue.

  Wang J., Chai X., Eriksson U., Napoli J.L.

  This report describes the activity of recombinant human Rdh5 (11-cis-retinol dehydrogenase) with steroids and retinoids and expression of the Rdh5 mRNA in extra-ocular human tissue. The data show that Rdh5 catalyses 9-cis-retinol metabolism equally efficiently as 11-cis-retinol metabolism and reco ... >> More

  This report describes the activity of recombinant human Rdh5 (11-cis-retinol dehydrogenase) with steroids and retinoids and expression of the Rdh5 mRNA in extra-ocular human tissue. The data show that Rdh5 catalyses 9-cis-retinol metabolism equally efficiently as 11-cis-retinol metabolism and recognizes 5alpha-androstan-3alpha,17beta-diol and androsterone as substrates (3alpha-hydroxysteroid dehydrogenase activity), but not testosterone, dihydrotestosterone, oestradiol and corticosterone (lack of 17beta-hydroxysteroid and 11beta-hydroxysteroid dehydrogenase activities). Rdh5 mRNA expression was widespread in extra-ocular tissues with human liver (100% relative expression in extra-ocular tissues only) and mammary gland (97% relative to liver) showing the most intense signals. Other noteworthy relatively intense expression sites included colon (45%), thymus (43%), small intestine (39%), kidney (37%), bladder (29%), pancreas and spleen (28% each), heart (26%), uterus and ovary (25% each), testis (22%) and spinal cord (24%). Human fetal tissues also expressed Rdh5 with fetal liver showing the most intense expression among the fetal tissues (20%). Considered along with the identical nucleotide sequences in the untranslated regions of human Rdh5 and human 9-cis-retinol dehydrogenase cDNAs and the nearly identical nucleotide sequences overall (99% identity), the current results suggest that the two cDNAs represent a single gene product. << Less

  Biochem. J. 338:23-27(1999) [PubMed] [EuropePMC]

  This publication is cited by 2 other entries.

• Retinoids, omega-hydroxyfatty acids and cytotoxic aldehydes as physiological substrates, and H2-receptor antagonists as pharmacological inhibitors, of human class IV alcohol dehydrogenase.

  Allali-Hassani A., Peralba J.M., Martras S., Farres J., Pares X.

  Kinetic constants of human class IV alcohol dehydrogenase (sigmasigma-ADH) support a role of the enzyme in retinoid metabolism, fatty acid omega-oxidation, and elimination of cytotoxic aldehydes produced by lipid peroxidation. Class IV is the human ADH form most efficient in the reduction of 4-hyd ... >> More

  Kinetic constants of human class IV alcohol dehydrogenase (sigmasigma-ADH) support a role of the enzyme in retinoid metabolism, fatty acid omega-oxidation, and elimination of cytotoxic aldehydes produced by lipid peroxidation. Class IV is the human ADH form most efficient in the reduction of 4-hydroxynonenal (k(cat)/Km: 39,500 mM(-1) min(-1)). Class IV shows high activity with all-trans-retinol and 9-cis-retinol, while 13-cis-retinol is not a substrate but an inhibitor. Both all-trans-retinoic and 13-cis-retinoic acids are potent competitive inhibitors of retinol oxidation (Ki: 3-10 microM) which can be a basis for the regulation of the retinoic acid generation and of the pharmacological actions of the 13-cis-isomer. The inhibition of class IV retinol oxidation by ethanol (Ki: 6-10 mM) may be the origin of toxic and teratogenic effects of ethanol. H2-receptor antagonists are poor inhibitors of human and rat classes I and IV (Ki > 0.3 mM) suggesting a small interference in ethanol metabolism at the pharmacological doses of these common drugs. << Less

  FEBS Lett. 426:362-366(1998) [PubMed] [EuropePMC]

  This publication is cited by 7 other entries.

• Biochemical properties, tissue expression, and gene structure of a short chain dehydrogenase/reductase able to catalyze cis-retinol oxidation.

  Gamble M.V., Shang E., Zott R.P., Mertz J.R., Wolgemuth D.J., Blaner W.S.

  We have identified a retinol dehydrogenase (cRDH) that catalyzes the oxidation of 9-cis-but not all-trans-retinol and proposed that this enzyme plays an important role in synthesis of the transcriptionally active retinoid, 9-cis-retinoic acid. There is little information regarding either the bioch ... >> More

  We have identified a retinol dehydrogenase (cRDH) that catalyzes the oxidation of 9-cis-but not all-trans-retinol and proposed that this enzyme plays an important role in synthesis of the transcriptionally active retinoid, 9-cis-retinoic acid. There is little information regarding either the biochemical properties of cRDH or how its 9-cis-retinol substrate is formed. We now report studies of the properties and expression of human and mouse cRDH and of the characteristics and location of the murine cRDH gene. Additionally, we report mouse hepatic 9-cis-retinol concentrations and demonstrate that 9-cis-retinol is formed in a time- and protein-dependent manner upon incubation of all-trans -retinol with cell homogenate. Human and mouse cRDH display similar substrate specificities for cis-isomers of retinol and retinaldehyde. Moreover, human and mouse cRDH show marked sensitivity to inhibition by 13-cis-retinoic acid, with both being inhibited by approximately 50% by 0.15 microm 13-cis-retinoic acid (for substrate concentrations of 10 microm). Lesser inhibition is seen for 9-cis- or all-trans-retinoic acids. Immunoblot analysis using antiserum directed against human cRDH demonstrates cRDH expression in several tissues from first trimester human fetuses, indicating that cRDH is expressed early in embryogenesis. Adult mouse brain, liver, kidney, and to a lesser extent small intestine and placenta express cRDH. The murine cRDH gene consists of at least 5 exons and spans approximately 6 kb of genomic DNA. Backcross analysis mapped the mouse cRDH gene to the most distal region of chromosome 10. Taken together, these data extend our understanding of the properties of cRDH and provide additional support for our hypothesis that cRDH may play an important role in 9-cis-retinoic acid formation. << Less

  J. Lipid Res. 40:2279-2292(1999) [PubMed] [EuropePMC]

  This publication is cited by 3 other entries.

• The identification of a 9-cis retinol dehydrogenase in the mouse embryo reveals a pathway for synthesis of 9-cis retinoic acid.

  Romert A., Tuvendal P., Simon A., Dencker L., Eriksson U.

  The ligand-controlled retinoic acid (RA) receptors and retinoid X receptors are important for several physiological processes, including normal embryonic development, but little is known about how their ligands, all-trans and 9-cis RA, are generated. Here we report the identification of a stereo-s ... >> More

  The ligand-controlled retinoic acid (RA) receptors and retinoid X receptors are important for several physiological processes, including normal embryonic development, but little is known about how their ligands, all-trans and 9-cis RA, are generated. Here we report the identification of a stereo-specific 9-cis retinol dehydrogenase, which is abundantly expressed in embryonic tissues known to be targets in the retinoid signaling pathway. The membrane-bound enzyme is a member of the short-chain alcohol dehydrogenase/reductase superfamily, able to oxidize 9-cis retinol into 9-cis retinaldehyde, an intermediate in 9-cis RA biosynthesis. Analysis by nonradioactive in situ hybridization in mouse embryos shows that expression of the enzyme is temporally and spatially well controlled during embryogenesis with prominent expression in parts of the developing central nervous system, sensory organs, somites and myotomes, and several tissues of endodermal origin. The identification of this enzyme reveals a pathway in RA biosynthesis, where 9-cis retinol is generated for subsequent oxidation to 9-cis RA. << Less

  Proc. Natl. Acad. Sci. U.S.A. 95:4404-4409(1998) [PubMed] [EuropePMC]

  This publication is cited by 1 other entry.

• The visual cycle retinol dehydrogenase: possible involvement in the 9-cis retinoic acid biosynthetic pathway.

  Driessen C.A., Winkens H.J., Kuhlmann E.D., Janssen A.P., van Vugt A.H., Deutman A.F., Janssen J.J.

  The 11-cis-retinol dehydrogenase (11-cis-RoDH) gene encodes the short-chain alcohol dehydrogenase responsible for 11-cis-retinol oxidation in the visual cycle. The structure of the murine 11-cis-RoDH gene was used to reinvestigate its transcription pattern. An 11-cis-RoDH gene transcript was detec ... >> More

  The 11-cis-retinol dehydrogenase (11-cis-RoDH) gene encodes the short-chain alcohol dehydrogenase responsible for 11-cis-retinol oxidation in the visual cycle. The structure of the murine 11-cis-RoDH gene was used to reinvestigate its transcription pattern. An 11-cis-RoDH gene transcript was detected in several non-ocular tissues. The question regarding the substrate specificity of the enzyme was therefore addressed. Recombinant 11-cis-RoDH was found capable of oxidizing and reducing 9-cis-, 11-cis- and 13-cis-isomers of retinol and retinaldehyde, respectively. Dodecyl-beta-1-maltoside used to solubilize the enzyme was found to affect the substrate specificity. This is the first report on a visual cycle enzyme also present in non-retinal ocular and non-ocular tissues. A possible role in addition to its role in the visual cycle is being discussed. << Less

  FEBS Lett. 428:135-140(1998) [PubMed] [EuropePMC]

  This publication is cited by 3 other entries.

• Alcohol dehydrogenase 2 is a major hepatic enzyme for human retinol metabolism.

  Hellgren M., Stroemberg P., Gallego O., Martras S., Farres J., Persson B., Pares X., Hoeoeg J.O.

  The metabolism of all-trans- and 9-cis-retinol/ retinaldehyde has been investigated with focus on the activities of human, mouse and rat alcohol dehydrogenase 2 (ADH2), an intriguing enzyme with apparently different functions in human and rodents. Kinetic constants were determined with an HPLC met ... >> More

  The metabolism of all-trans- and 9-cis-retinol/ retinaldehyde has been investigated with focus on the activities of human, mouse and rat alcohol dehydrogenase 2 (ADH2), an intriguing enzyme with apparently different functions in human and rodents. Kinetic constants were determined with an HPLC method and a structural approach was implemented by in silico substrate dockings. For human ADH2, the determined K(m) values ranged from 0.05 to 0.3 microM and k(cat) values from 2.3 to 17.6 min(-1), while the catalytic efficiency for 9-cis-retinol showed the highest value for any substrate. In contrast, poor activities were detected for the rodent enzymes. A mouse ADH2 mutant (ADH2Pro47His) was studied that resembles the human ADH2 setup. This mutation increased the retinoid activity up to 100-fold. The K(m) values of human ADH2 are the lowest among all known human retinol dehydrogenases, which clearly support a role in hepatic retinol oxidation at physiological concentrations. << Less

  Cell. Mol. Life Sci. 64:498-505(2007) [PubMed] [EuropePMC]

  This publication is cited by 1 other entry.