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Norman E. Sladek

Bio: Norman E. Sladek is an academic researcher from University of Minnesota. The author has contributed to research in topics: Aldehyde dehydrogenase & Aldophosphamide. The author has an hindex of 24, co-authored 51 publications receiving 2082 citations.


Papers
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Journal ArticleDOI
TL;DR: The absence of a fully functional first category aldehyde dehydrogenase results in a gross pathological phenotype in the absence of any insult, whereas the lack of a functional second category aLDNase is ordinarily of no consequence with respect to gross phenotype, but is of consequence in that regard when the organism is subjected to a relevant insult.
Abstract: Aldehyde dehydrogenases catalyze the pyridine nucleotide-dependent oxidation of aldehydes to acids. Seventeen enzymes are currently viewed as belonging to the human aldehyde dehydrogenase superfamily. Summarized herein, insofar as the information is available, are the structural composition, physical properties, tissue distribution, subcellular location, substrate specificity, and cofactor preference of each member of this superfamily. Also summarized are the chromosomal locations and organization of the genes that encode these enzymes and the biological consequences when enzyme activity is lost or substantially diminished. Broadly, aldehyde dehydrogenases can be categorized as critical for normal development and/or physiological homeostasis (1) even when the organism is in a friendly environment or (2) only when the organism finds itself in a hostile environment. The primary, if not sole, evolved raison d'etre of first category aldehyde dehydrogenases appears to be to catalyze the biotransformation of a single endobiotic for which they are relatively specific and of which the resultant metabolite is essential to the organism. Most of the human aldehyde dehydrogenases for which the relevant information is available fall into this category. Second category aldehyde dehydrogenases are relatively substrate nonspecific and their evolved raison d'etre seems to be to protect the organism from potentially harmful xenobiotics, specifically aldehydes or xenobiotics that give rise to aldehydes, by catalyzing their detoxification. Thus, the lack of a fully functional first category aldehyde dehydrogenase results in a gross pathological phenotype in the absence of any insult, whereas the lack of a functional second category aldehyde dehydrogenase is ordinarily of no consequence with respect to gross phenotype, but is of consequence in that regard when the organism is subjected to a relevant insult. © 2003 Wiley Periodicals, Inc. J Biochem Mol Toxicol 17:7–23, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.10057

261 citations

Journal ArticleDOI
TL;DR: Measurement of ALDH1A1 levels in primary breast malignancies and/or normal breast tissue prior to the initiation of chemotherapy is likely to be of value in predicting the therapeutic potential, or lack of potential, of cyclophosphamide and other oxazaphosphorines.
Abstract: Purpose: In preclinical models, established molecular determinants of cellular sensitivity to cyclophosphamide, long a mainstay of chemotherapeutic regimens used to treat breast cancers, include the aldehyde dehydrogenases that catalyze the detoxification of this agent, namely, ALDH1A1 and ALDH3A1. As judged by bulk quantification of relevant catalytic activities, as well as of relevant proteins (ELISAs), tissue levels of these enzymes vary widely in primary and metastatic breast malignancies. Thus, interindividual variation in the activity of either of these enzymes in breast cancers could contribute to the wide variation in clinical responses obtained when such regimens are used to treat these malignancies. Direct evidence for this notion was sought in the present investigation. Methods: Cellular levels of ALDH1A1 and ALDH3A1 in 171 repository human breast tumor (122 primary and 49 metastatic) samples were semiquantified using immunocytochemical staining. Clinical responses were retrieved from the archived medical records of each of 48 metastatic breast cancer sample donors, 26 of whom had been treated with a cyclophosphamide-based chemotherapeutic regimen subsequent to tumor sampling and 22 of whom had not. The premise that cellular levels of ALDH1A1 and/or ALDH3A1 predict clinical responses to cyclophosphamide-based chemotherapeutic regimens was submitted to statistical analysis. Results: Confirming an earlier report, ALDH1A1 and ALDH3A1 levels varied widely in both primary and metastatic breast tumor cells. When measurably present, each of the enzymes appeared to be evenly distributed throughout a given tumor cell population. Retrospective analysis indicated that cellular levels of ALDH1A1, but not those of ALDH3A1, were (1) significantly higher in metastatic tumor cells that had survived exposure to cyclophosphamide than in those that had not been exposed to this drug, and (2) significantly higher in metastatic tumors that did not respond (tumor size did not decrease or even increased) to subsequent treatment with cyclophosphamide-based chemotherapeutic regimens than in those that did respond (tumor size decreased) to such regimens. The therapeutic outcome of cyclophosphamide-based chemotherapy corresponded to cellular ALDH1A1 levels in 77% of cases. The frequencies of false-positives (cyclophosphamide-based chemotherapy not effective when a low level of ALDH1A1 predicted it would be) and false-negatives (cyclophosphamide-based chemotherapy effective when a high level of ALDH1A1 predicted it would not be) were 0.00 and 0.43, respectively. Thus, partial or complete responses to cyclophosphamide-based chemotherapy occurred 2.3 times more often when the ALDH1A1 level was low than when it was high. Conclusions: Given (1) the wide range of ALDH1A1 levels observed in malignant breast tissues, (2) that ALDH1A1 levels in primary breast tumor tissue, as well as those in normal breast tissue, directly reflect ALDH1A1 levels in metastatic breast tumor cells derived therefrom, and (3) the findings reported here, measurement of ALDH1A1 levels in primary breast malignancies and/or normal breast tissue prior to the initiation of chemotherapy is likely to be of value in predicting the therapeutic potential, or lack of potential, of cyclophosphamide and other oxazaphosphorines, e.g. ifosfamide, in the treatment of primary, as well as metastatic, breast cancer, thus providing a rational basis for the design of individualized therapeutic regimens for this disease. Failure to observe the expected inverse relationship between clinical responses to cyclophosphamide-based chemotherapeutic regimens and ALDH3A1 levels was probably because even the highest breast tumor tissue ALDH3A1 level thus far reported appears to be below the threshold level at which ALDH3A1-catalyzed detoxification of oxazaphosphorines becomes pharmacologically meaningful. However, ALDH3A1 levels in certain other malignancies, e.g. those of the alimentary tract and lung, may be of a sufficient magnitude in that regard.

204 citations

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TL;DR: Seven aldehyde dehydrogenases found in the cytosol of mouse stomach epithelium and cornea catalyzed the oxidation of retinaldehyde to retinoic acid, a metabolite of vitamin A that promotes the differentiation of epithelial and other cells.

151 citations

Journal ArticleDOI
TL;DR: Observations strongly suggest an important in vivo role for ALDH-1 in the catalysis of retinaldehyde and aldophosphamide biotransformation and that succinic semialdehyde dehydrogenase-catalyzed biOTransformation of aldphosphamide may also be of some in vivo importance.

144 citations

Journal Article
TL;DR: In this article, the salivary content of these enzymes was found to be increased upon daily consumption of relatively large amounts of coffee or broccoli, indicating that these enzymes are abundantly present in the human diet, especially in certain vegetables and fruits.
Abstract: Human saliva was tested for the presence of cytosolic class 3 aldehyde dehydrogenase, glutathione S-transferases alpha, mu, and pi, and DT-diaphorase, enzymes that are known to catalyze the biotransformation of many xenobiotics, including some that are carcinogens and some that are antineoplastic agents. Each of these enzymes was found to be present in this fluid. Inducers of these enzymes are known to be abundantly present in the human diet, especially in certain vegetables and fruits. Further investigation revealed that the salivary content of these enzymes rapidly, coordinately, and markedly increased upon daily consumption of relatively large amounts of coffee or broccoli. The enzyme activities of interest rapidly returned to basal levels when these substances were removed from the diet. Given the important role that cytosolic class 3 aldehyde dehydrogenase, the glutathione S-transferases, and DT-diaphorase are thought to play in determining the carcinogenic potential of some cancer-producing agents as well as the cytotoxic potential of some antineoplastic agents, and assuming that their salivary levels reflect their tissue levels, quantification of the salivary content of one or more of these enzymes, a noninvasive and relatively easy undertaking, could be useful in: (a) preliminarily assessing the chemopreventive potential of various diets and drugs; (b) establishing the optimal dose and schedule in Phase I clinical trials for any putatively chemopreventive diets or drugs of interest; and (c) the rational selection and use of chemotherapeutic agents, since several are inactivated, and a few are activated, by these enzymes; alternatively, the antineoplastic agent could be selected first and then a diet that enables the agent to achieve its full therapeutic potential would be selected based on whether high or low enzyme activity would be favorable in that regard. Such measurements may also be useful as an indicator when exposure to carcinogenic/teratogenic/otherwise toxic environmental/industrial/dietary agents that induce these enzymes is suspected.

100 citations


Cited by
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David R. Janero1
TL;DR: The conclusion is reached that MDA determination and the TBA test can offer, at best, a narrow and somewhat empirical window on the complex process of lipid peroxidation.

2,540 citations

Journal Article
TL;DR: This investigation expands the horizon of Nrf2-regulated genes, highlights the cross-talk between various metabolic pathways, and divulges the pivotal role played by NRF2 in regulating cellular defenses against carcinogens and other toxins.
Abstract: Electrophiles formed during metabolic activation of chemical carcinogens and reactive oxygen species generated from endogenous and exogenous sources play a significant role in carcinogenesis. Cancer chemoprevention by induction of phase 2 proteins to counteract the insults of these reactive intermediates has gained considerable attention. Nuclear factor E2 p45-related factor 2 (Nrf2), a bZIP transcription factor, plays a central role in the regulation (basal and or inducible expression) of phase 2 genes by binding to the “antioxidant response element” in their promoters. Identification of novel Nrf2-regulated genes is likely to provide insight into cellular defense systems against the toxicities of electrophiles and oxidants and may define effective targets for achieving cancer chemoprevention. Sulforaphane is a promising chemopreventive agent that exerts its effect by strong induction of phase 2 enzymes via activation of Nrf2. In the present study, a transcriptional profile of small intestine of wild-type (nrf2 +/+) and knock out (nrf2 −/−) mice treated with vehicle or sulforaphane (9 μmol/day for 1 week, p.o.) was generated using the Murine Genome U74Av2 oligonucleotide array (representing ∼6000 well-characterized genes and nearly 6000 expressed sequence tags). Comparative analysis of gene expression changes between different treatment groups of wild-type and nrf2-deficient mice facilitated identification of numerous genes regulated by Nrf2 including previously reported Nrf2-regulated genes such as NAD(P)H:quinone reductase (NQO1), glutathione S-transferase (GST), γ-glutamylcysteine synthetase (GCS), UDP-glucuronosyltransferases (UGT),epoxide hydrolase, as well as a number of new genes. Also identified were genes encoding for cellular NADPH regenerating enzymes (glucose 6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, and malic enzyme), various xenobiotic metabolizing enzymes, antioxidants (glutathione peroxidase, glutathione reductase, ferritin, and haptaglobin), and biosynthetic enzymes of the glutathione and glucuronidation conjugation pathways. The data were validated by Northern blot analysis and enzyme assays of selected genes. This investigation expands the horizon of Nrf2-regulated genes, highlights the cross-talk between various metabolic pathways, and divulges the pivotal role played by Nrf2 in regulating cellular defenses against carcinogens and other toxins.

1,186 citations

Journal ArticleDOI
TL;DR: It is speculated that hexose-6-phosphate dehydrogenase activity and therefore reduced nicotinamide-adenine dinucleotide phosphate supply may be crucial in determining the directionality of 11beta-HSD1 activity.
Abstract: 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) interconverts inactive cortisone and active cortisol. Although bidirectional, in vivo it is believed to function as a reductase generating active glucocorticoid at a prereceptor level, enhancing glucocorticoid receptor activation. In this review, we discuss both the genetic and enzymatic characterization of 11beta-HSD1, as well as describing its role in physiology and pathology in a tissue-specific manner. The molecular basis of cortisone reductase deficiency, the putative "11beta-HSD1 knockout state" in humans, has been defined and is caused by intronic mutations in HSD11B1 that decrease gene transcription together with mutations in hexose-6-phosphate dehydrogenase, an endoluminal enzyme that provides reduced nicotinamide-adenine dinucleotide phosphate as cofactor to 11beta-HSD1 to permit reductase activity. We speculate that hexose-6-phosphate dehydrogenase activity and therefore reduced nicotinamide-adenine dinucleotide phosphate supply may be crucial in determining the directionality of 11beta-HSD1 activity. Therapeutic inhibition of 11beta-HSD1 reductase activity in patients with obesity and the metabolic syndrome, as well as in glaucoma and osteoporosis, remains an exciting prospect.

989 citations

Journal ArticleDOI
TL;DR: The key role of vitamin A in embryonal development is reviewed and special emphasis is given to the physiological action of retinoids, as evident from the retinoid ligand knockout models.
Abstract: The key role of vitamin A in embryonal development is reviewed. Special emphasis is given to the physiological action of retinoids, as evident from the retinoid ligand knockout models. Retinoid metabolism in embryonic tissues and teratogenic consequences of retinoid administration at high doses are presented. Physiological and pharmacological actions of retinoids are outlined and explained on the basis of their interactions as ligands of the nuclear retinoid receptors. Immediate target genes and the retinoid response elements of their promoters are summarized. The fundamental role of homeobox genes in embryonal development and the actions of retinoids on their expression are discussed. The similarity of the effects of retinoid ligand knockouts to effects of compound retinoid receptor knockouts on embryogenesis is presented. Although much remains to be clarified, the emerging landscape offers exciting views for future research.

849 citations

Journal ArticleDOI
TL;DR: Experimental dietary studies in humans showed the capacity of vegetables and fruit and their constituents to modulate some of these potential disease-preventive mechanisms, including modulation of detoxification enzymes, stimulation of the immune system, and reduction of platelet aggregation.

758 citations