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Featured researches published by Satori A. Marchitti.


Expert Opinion on Drug Metabolism & Toxicology | 2008

Non-P450 aldehyde oxidizing enzymes: the aldehyde dehydrogenase superfamily

Satori A. Marchitti; Chad Brocker; Dimitrios Stagos; Vasilis Vasiliou

Background: Aldehydes are highly reactive molecules. While several non-P450 enzyme systems participate in their metabolism, one of the most important is the aldehyde dehydrogenase (ALDH) superfamily, composed of NAD(P)+-dependent enzymes that catalyze aldehyde oxidation. Objective: This article presents a review of what is currently known about each member of the human ALDH superfamily including the pathophysiological significance of these enzymes. Methods: Relevant literature involving all members of the human ALDH family was extensively reviewed, with the primary focus on recent and novel findings. Conclusion: To date, 19 ALDH genes have been identified in the human genome and mutations in these genes and subsequent inborn errors in aldehyde metabolism are the molecular basis of several diseases, including Sjögren-Larsson syndrome, type II hyperprolinemia, γ-hydroxybutyric aciduria and pyridoxine-dependent seizures. ALDH enzymes also play important roles in embryogenesis and development, neurotransmission, oxidative stress and cancer. Finally, ALDH enzymes display multiple catalytic and non-catalytic functions including ester hydrolysis, antioxidant properties, xenobiotic bioactivation and UV light absorption.


Pharmacological Reviews | 2007

Neurotoxicity and Metabolism of the Catecholamine-Derived 3,4-Dihydroxyphenylacetaldehyde and 3,4-Dihydroxyphenylglycolaldehyde: The Role of Aldehyde Dehydrogenase

Satori A. Marchitti; Richard A. Deitrich; Vasilis Vasiliou

Aldehydes are highly reactive molecules formed during the biotransformation of numerous endogenous and exogenous compounds, including biogenic amines. 3,4-Dihydroxyphenylacetaldehyde is the aldehyde metabolite of dopamine, and 3,4-dihydroxyphenylglycolaldehyde is the aldehyde metabolite of both norepinephrine and epinephrine. There is an increasing body of evidence suggesting that these compounds are neurotoxic, and it has been recently hypothesized that neurodegenerative disorders may be associated with increased levels of these biogenic aldehydes. Aldehyde dehydrogenases are a group of NAD(P)+-dependent enzymes that catalyze the oxidation of aldehydes, such as those derived from catecholamines, to their corresponding carboxylic acids. To date, 19 aldehyde dehydrogenase genes have been identified in the human genome. Mutations in these genes and subsequent inborn errors in aldehyde metabolism are the molecular basis of several diseases, including Sjögren-Larsson syndrome, type II hyperprolinemia, γ-hydroxybutyric aciduria, and pyridoxine-dependent seizures, most of which are characterized by neurological abnormalities. Several pharmaceutical agents and environmental toxins are also known to disrupt or inhibit aldehyde dehydrogenase function. It is, therefore, possible to speculate that reduced detoxification of 3,4-dihydroxyphenylacetaldehyde and 3,4-dihydroxyphenylglycolaldehyde from impaired or deficient aldehyde dehydrogenase function may be a contributing factor in the suggested neurotoxicity of these compounds. This article presents a comprehensive review of what is currently known of both the neurotoxicity and respective metabolism pathways of 3,4-dihydroxyphenylacetaldehyde and 3,4-dihydroxyphenylglycolaldehyde with an emphasis on the role that aldehyde dehydrogenase enzymes play in the detoxification of these two aldehydes.


Circulation Research | 2009

Metabolic Remodeling Induced by Mitochondrial Aldehyde Stress Stimulates Tolerance to Oxidative Stress in the Heart

Jin Endo; Motoaki Sano; Takaharu Katayama; Takako Hishiki; Ken Shinmura; Shintaro Morizane; Tomohiro Matsuhashi; Yoshinori Katsumata; Yan Zhang; Hideyuki Ito; Yoshiko Nagahata; Satori A. Marchitti; Kiyomi Nishimaki; Alexander M. Wolf; Hiroki Nakanishi; Fumiyuki Hattori; Vasilis Vasiliou; Takeshi Adachi; Ikuroh Ohsawa; Ryo Taguchi; Yoshio Hirabayashi; Shigeo Ohta; Makoto Suematsu; Satoshi Ogawa; Keiichi Fukuda

Rationale: Aldehyde accumulation is regarded as a pathognomonic feature of oxidative stress–associated cardiovascular disease. Objective: We investigated how the heart compensates for the accelerated accumulation of aldehydes. Methods and Results: Aldehyde dehydrogenase 2 (ALDH2) has a major role in aldehyde detoxification in the mitochondria, a major source of aldehydes. Transgenic (Tg) mice carrying an Aldh2 gene with a single nucleotide polymorphism (Aldh2*2) were developed. This polymorphism has a dominant-negative effect and the Tg mice exhibited impaired ALDH activity against a broad range of aldehydes. Despite a shift toward the oxidative state in mitochondrial matrices, Aldh2*2 Tg hearts displayed normal left ventricular function by echocardiography and, because of metabolic remodeling, an unexpected tolerance to oxidative stress induced by ischemia/reperfusion injury. Mitochondrial aldehyde stress stimulated eukaryotic translation initiation factor 2&agr; phosphorylation. Subsequent translational and transcriptional activation of activating transcription factor-4 promoted the expression of enzymes involved in amino acid biosynthesis and transport, ultimately providing precursor amino acids for glutathione biosynthesis. Intracellular glutathione levels were increased 1.37-fold in Aldh2*2 Tg hearts compared with wild-type controls. Heterozygous knockout of Atf4 blunted the increase in intracellular glutathione levels in Aldh2*2 Tg hearts, thereby attenuating the oxidative stress–resistant phenotype. Furthermore, glycolysis and NADPH generation via the pentose phosphate pathway were activated in Aldh2*2 Tg hearts. (NADPH is required for the recycling of oxidized glutathione.) Conclusions: The findings of the present study indicate that mitochondrial aldehyde stress in the heart induces metabolic remodeling, leading to activation of the glutathione–redox cycle, which confers resistance against acute oxidative stress induced by ischemia/reperfusion.


Toxicological Sciences | 2012

Human and Rat ABC Transporter Efflux of Bisphenol A and Bisphenol A Glucuronide: Interspecies Comparison and Implications for Pharmacokinetic Assessment

Christopher S. Mazur; Satori A. Marchitti; Mira Dimova; John F. Kenneke; Annie Lumen; Jeff Fisher

Significant interspecies differences exist between human and rodent with respect to absorption, distribution, and excretion of bisphenol A (BPA) and its primary metabolite, BPA-glucuronide (BPA-G). ATP-Binding Cassette (ABC) transporter enzymes play important roles in these physiological processes, and their enzyme localization (apical vs. basolateral) in the plasma membrane allows for different cellular efflux pathways. In this study, we utilized an ATPase assay to evaluate BPA and BPA-G as potential substrates for the human and rat ABC transporters: P-glycoprotein (MDR1), multidrug resistance-associated proteins (MRPs), and breast cancer-resistant protein (BCRP). Based on high ATPase activity, BPA is likely a substrate for rat mdr1b but not for human MDR1 or rat mdr1a. Results indicate that BPA is a potential substrate for rat mrp2 and human MRP2, BCRP, and MRP3. The metabolite BPA-G demonstrated the highest apparent substrate binding affinity for rat mrp2 and human MRP3 but appeared to be a nonsubstrate or potential inhibitor for human MRP2, MDR1, and BCRP and for rat mdr1a, mdr1b, and bcrp. Analysis of ABC transporter amino acid sequences revealed key differences in putative binding site composition that may explain substrate specificity. Collectively, these results suggest that in both rat and human, apical transporters efflux BPA into the bile and/or intestinal lumen. BPA-G would follow a similar pathway in rat; however, in human, due to the basolateral location of MRP3, BPA-G would likely enter systemic and portal blood supplies. These differences between human and rodent ABC transporters may have significant implications for interspecies extrapolation used in risk assessment.


Pharmacogenetics and Genomics | 2009

Human aldehyde dehydrogenase genes: alternatively spliced transcriptional variants and their suggested nomenclature

William J. Black; Dimitrios Stagos; Satori A. Marchitti; Daniel W. Nebert; Keith F. Tipton; Amos Marc Bairoch; Vasilis Vasiliou

Objective The human aldehyde dehydrogenase (ALDH) gene superfamily consists of 19 genes encoding enzymes critical for NAD(P)+-dependent oxidation of endogenous and exogenous aldehydes, including drugs and environmental toxicants. Mutations in ALDH genes are the molecular basis of several disease states (e.g. Sjögren-Larsson syndrome, pyridoxine-dependent seizures, and type II hyperprolinemia) and may contribute to the etiology of complex diseases such as cancer and Alzheimers disease. The aim of this nomenclature update was to identify splice transcriptional variants principally for the human ALDH genes. Methods Data-mining methods were used to retrieve all human ALDH sequences. Alternatively spliced transcriptional variants were determined based on (i) criteria for sequence integrity and genomic alignment; (ii) evidence of multiple independent cDNA sequences corresponding to a variant sequence; and (iii) if available, empirical evidence of variants from the literature. Results and conclusion Alternatively spliced transcriptional variants and their encoded proteins exist for most of the human ALDH genes; however, their function and significance remain to be established. When compared with the human genome, rat and mouse include an additional gene, Aldh1a7, in the ALDH1A subfamily. To avoid confusion when identifying splice variants in various genomes, nomenclature guidelines for the naming of such alternative transcriptional variants and proteins are recommended herein. In addition, a web database (www.aldh.org) has been developed to provide up-to-date information and nomenclature guidelines for the ALDH superfamily.


Journal of Histochemistry and Cytochemistry | 2010

Aldehyde Dehydrogenase 3B1 (ALDH3B1): Immunohistochemical Tissue Distribution and Cellular-specific Localization in Normal and Cancerous Human Tissues

Satori A. Marchitti; David J. Orlicky; Chad Brocker; Vasilis Vasiliou

Aldehyde dehydrogenase (ALDH) enzymes are critical in the detoxification of endogenous and exogenous aldehydes. Our previous findings indicate that the ALDH3B1 enzyme is expressed in several mouse tissues and is catalytically active toward aldehydes derived from lipid peroxidation, suggesting a potential role against oxidative stress. The aim of this study was to elucidate by immunohistochemistry the tissue, cellular, and subcellular distribution of ALDH3B1 in normal human tissues and in tumors of human lung, colon, breast, and ovary. Our results indicate that ALDH3B1 is expressed in a tissue-specific manner and in a limited number of cell types, including hepatocytes, proximal convoluted tubule cells, cerebellar astrocytes, bronchiole ciliated cells, testis efferent ductule ciliated cells, and histiocytes. ALDH3B1 expression was upregulated in a high percentage of human tumors (lung > breast = ovarian > colon). Increased ALDH3B1 expression in tumor cells may confer a growth advantage or be the result of an induction mechanism mediated by increased oxidative stress. Subcellular localization of ALDH3B1 was predominantly cytosolic in tissues, with the exception of normal human lung and testis, in which localization appeared membrane-bound or membrane-associated. The specificity of ALDH3B1 distribution may prove to be directly related to the functional role of this enzyme in human tissues.


Eye & Contact Lens-science and Clinical Practice | 2011

Ultraviolet Radiation: Cellular Antioxidant Response and the Role of Ocular Aldehyde Dehydrogenase Enzymes

Satori A. Marchitti; Ying Chen; David C. Thompson; Vasilis Vasiliou

Solar ultraviolet radiation (UVR) exposes the human eye to near constant oxidative stress. Evidence suggests that UVR is the most important environmental insult leading to the development of a variety of ophthalmoheliosis disorders. UVR-induced reactive oxygen species (ROS) are highly reactive with DNA, proteins, and cellular membranes, resulting in cellular and tissue damage. Antioxidant defense systems present in ocular tissues function to combat ROS and protect the eye from oxidative damage. Important enzymatic antioxidants are the superoxide dismutases, catalase, glutathione peroxidases, glutathione reductase, and members of the aldehyde dehydrogenase (ALDH) superfamily. Glutathione, ascorbic and uric acids, α-tocopherol, nicotinamide-adenine dinucleotide phosphate, and ferritin serve as small molecule, nonenzymatic antioxidants. Ocular tissues have high levels of these antioxidants, which are essential for the maintenance of reduction-oxidation homeostasis in the eye and protection against oxidative damage. ALDH1A1 and ALDH3A1, present abundantly in the cornea and lens, have been shown to have unique roles in the defense against UVR and the downstream effects of oxidative stress. This review presents the properties and functions of ocular antioxidants that play critical roles in the cellular response to UVR exposure, including a focused discussion of the unique roles that the ALDH1A1 and ALDH3A1 enzymes have as multifunctional ocular antioxidants.


Free Radical Biology and Medicine | 2010

Molecular Characterization, Expression Analysis and Role of ALDH3B1 in The Cellular Protection Against Oxidative Stress

Satori A. Marchitti; Chad Brocker; David J. Orlicky; Vasilis Vasiliou

Aldehyde dehydrogenase (ALDH) enzymes are critical in the detoxification of aldehydes. The human genome contains 19 ALDH genes, mutations in which are the basis of several diseases. The expression, subcellular localization, enzyme kinetics, and role of ALDH3B1 in aldehyde- and oxidant-induced cytotoxicity were investigated. ALDH3B1 was purified from Sf9 cells using chromatographic methods, and enzyme kinetics were determined spectrophotometrically. ALDH3B1 demonstrated high affinity for hexanal (K(m)=62 μM), octanal (K(m)=8 μM), 4-hydroxy-2-nonenal (4HNE; K(m)=52 μM), and benzaldehyde (K(m)=46 μM). Low affinity was seen toward acetaldehyde (K(m)=23.3 mM), malondialdehyde (K(m)=152 mM), and the ester p-nitrophenyl acetate (K(m)=3.6 mM). ALDH3B1 mRNA was abundant in testis, lung, kidney, and ovary. ALDH3B1 protein was highly expressed in these tissues and the liver. Immunofluorescence microscopy of ALDH3B1-transfected human embryonic kidney (HEK293) cells and subcellular fractionation of mouse kidney and liver revealed a cytosolic protein localization. ALDH3B1-transfected HEK293 cells were significantly protected from the lipid peroxidation-derived aldehydes trans-2-octenal, 4HNE, and hexanal and the oxidants H(2)O(2) and menadione. In addition, ALDH3B1 protein expression was up-regulated by 4HNE in ARPE-19 cells. The results detailed in this study support a pathophysiological role for ALDH3B1 in protecting cells from the damaging effects of oxidative stress.


Critical Reviews in Toxicology | 2014

Improving the risk assessment of lipophilic persistent environmental chemicals in breast milk

Geniece McCollum Lehmann; Marc-André Verner; Bryan Luukinen; Cara Henning; Sue Anne Assimon; Judy S. LaKind; Eva D. McLanahan; Linda Phillips; Matthew H. Davis; Christina M. Powers; Erin P. Hines; Sami Haddad; Matthew P. Longnecker; Michael T. Poulsen; David G. Farrer; Satori A. Marchitti; Yu Mei Tan; Jeffrey C. Swartout; Sharon K. Sagiv; Clement Welsh; Jerry L. Campbell; Warren G. Foster; Raymond S. H. Yang; Suzanne E. Fenton; Rogelio Tornero-Velez; Bettina M. Francis; John B. Barnett; Hisham A. El-Masri; Jane Ellen Simmons

Abstract Lipophilic persistent environmental chemicals (LPECs) have the potential to accumulate within a womans body lipids over the course of many years prior to pregnancy, to partition into human milk, and to transfer to infants upon breastfeeding. As a result of this accumulation and partitioning, a breastfeeding infants intake of these LPECs may be much greater than his/her mothers average daily exposure. Because the developmental period sets the stage for lifelong health, it is important to be able to accurately assess chemical exposures in early life. In many cases, current human health risk assessment methods do not account for differences between maternal and infant exposures to LPECs or for lifestage-specific effects of exposure to these chemicals. Because of their persistence and accumulation in body lipids and partitioning into breast milk, LPECs present unique challenges for each component of the human health risk assessment process, including hazard identification, dose–response assessment, and exposure assessment. Specific biological modeling approaches are available to support both dose–response and exposure assessment for lactational exposures to LPECs. Yet, lack of data limits the application of these approaches. The goal of this review is to outline the available approaches and to identify key issues that, if addressed, could improve efforts to apply these approaches to risk assessment of lactational exposure to these chemicals.


Environmental Science & Technology | 2013

Improving infant exposure and health risk estimates: using serum data to predict polybrominated diphenyl ether concentrations in breast milk.

Satori A. Marchitti; Judy S. LaKind; Daniel Q. Naiman; Cheston M. Berlin; John F. Kenneke

Women in the United States have breast milk concentrations of polybrominated diphenyl ethers (PBDEs) that are among the highest in the world, leading to concerns over the potential health implications to breastfeeding infants during critical stages of growth and development. Developing cost-effective and sustainable methods for assessing chemical exposures in infants is a high priority to federal agencies and local communities. PBDE data are available in nationally representative serum samples but not in breast milk. As a method to predict PBDE concentrations in U.S. breast milk, we present the development of congener-specific linear regression partitioning models and their application to U.S. serum data. Models were developed from existing paired milk and serum data and applied to 2003-2004 NHANES serum data for U.S. women. Highest estimated median U.S. breast milk concentrations were for BDE-47 (30.6 ng/g lipid) and BDE-99 (6.1 ng/g lipid) with the median concentration of Σ7PBDEs estimated at 54.2 ng/g lipid. Predictions of breast milk PBDE concentration were consistent with reported concentrations from 11 similarly timed U.S. studies. When applied to NHANES data, these models provide a sustainable method for estimating population-level concentrations of PBDEs in U.S. breast milk and should improve exposure estimates in breastfeeding infants.

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John F. Kenneke

United States Environmental Protection Agency

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Chad Brocker

National Institutes of Health

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Christopher S. Mazur

United States Environmental Protection Agency

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David C. Thompson

University of Colorado Boulder

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J. Mark Petrash

University of Colorado Denver

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Caleb M. Dillingham

United States Environmental Protection Agency

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