DBT Ramalingaswami Fellow,
Department of Chemistry,
School of Natural Sciences
Email Contact: Goutam.firstname.lastname@example.org
Ph.D. in Bioorganic Chemistry, University of Missouri-Columbia, USA.
M.Sc. in Biochemistry and Toxicology, University of Calcutta, WB, India
B.Sc. in Chemistry, University of Calcutta, WB, India
Staff Scientist, Covance Laboratories Inc. Madison, WI, USA
Research Instructor of Biochemistry, Vanderbilt University, Nashville, TN, USA
Postdoctoral Research Fellow of Biochemistry, Vanderbilt University, Nashville, TN, USA, Advisor: Prof. F. Peter Guengerich.
The Chowdhury lab works in the interface of chemistry and biology trying to understand at the molecular level the effect of small organic molecules on biological systems. The goal is to elucidate the molecular mechanism of toxicity of drugs, pesticides and carcinogen suspect agents. Specifically, we are interested in the metabolism/biotransformation of these agents by various enzymes including P450s, formation of reactive intermediates, its interaction with DNA and proteins, and the mutational and/or toxicological consequences. The Chowdhury lab is currently studying a diverse array of compounds including thalidomide, ethylene dibromide, and various derivatives of 8-NO2-G (8-nitroguanine, 8-nitroguanosine, and 8-nitro-cyclicGMP). Thalidomide is a teratogen that has been recently approved for the treatment of multiple myeloma and leprosy, ethylene dibromide is an environmental toxicant, and 8-NO2-G compounds are detected in vivo at sites of chronic inflammation.
Another area of interest is the development of predictive biomarkers of toxicity of reactive intermediates. Bioavailability and particularly toxicity are two of the most common barriers in drug development today, and drug metabolism can influence both. As a result of toxicity, 16 out of 548 new chemical entities that were approved for the US market were subsequently withdrawn and 56 acquired black box warning. Predicting toxicity is thus an important issue in the development of pharmaceuticals as it is with pesticides, cancer suspects, environmental pollutants, and drugs of abuse. The mechanisms by which chemicals exert toxic effects are complex. Formation of "reactive metabolites" has been implicated as a major cause of toxicity or adverse drug reactions. Reactive metabolites may interact with cellular macromolecules resulting in various biological outcomes including mutations, inflammation, and alteration of gene expression, protein functions, and cellular metabolism that may lead to adverse effects. Alternatively, interaction of reactive metabolites with cellular macromolecules may also lead to detoxification. There is no simple correlation between reactive metabolite formation and toxicity, and therefore, conventional methods including covalent binding and thioether adduct formation are not sufficient to predict the toxicological outcome in vivo. There is a knowledge gap between the formation of reactive metabolites and toxicity. The goals are to understand the molecular mechanism of toxicity associated with reactive metabolites and, in the process, identify potential predictive molecular biomarkers of toxicity.
The proposed projects of the Chowdhury laboratory involve multidisciplinary basic research with translational values. The findings will have the potential to contribute not only in the field of drug development but also towards understanding the possible cause of certain cancers and their early detection or risk assessment.
Chowdhury G, Shibata N, Yamazaki H and Guengerich, F. P. Human Cytochrome P450 oxidation of 5-hydroxythalidomide and pomalidomide, an amino analog of thalidomide. Chem. Res. Toxicol. 2013, 27, 147-156.
Chowdhury G, Cho SH, Pegg A and Guengerich, F. P. Detection and characterization of 1,2-dibromoethane-derived DNA crosslinks formed with O(6) -alkylguanine-DNA alkyltransferase.. Angew. Chem. Intl. Ed. 2013, 52, 12879-82. This paper has been selected as a very important paper.
Chowdhury G, Calcutt MW, Nagy LD, Guengerich FP. Oxidation of methyl and ethyl nitrosamines by cytochrome P450 2E1 and 2B1. Biochemistry 2012, 51, 9995-10007.
Chowdhury G, Sarker U, Pullen S, Wilson WR, Rajapakse A, Fuchs-Knotts T and Gates KS. DNA damage by the naturally-occurring heterocyclic N-oxide myxin under both aerobic and anaerobic conditions. Chem. Res. Toxicol. 2012, 25, 197-206.
Chowdhury G, Murayama N, Okada Y, Uno Y, Shimizu M, Guengerich FP, and Yamazaki H. Human Liver Microsomal Cytochrome P450 3A Enzymes Involved in Thalidomide 5-Hydroxylation and Formation of a Glutathione Conjugate. Chem. Res. Toxicol. 2010, 23, 1018-1024.
Chowdhury G, Calcutt MW and Guengerich FP. Oxidation of N-Nitrosoalkylamines by human cytochrome P450 2A6. J. Biol. Chem. 2010, 285, 8031-8044.
Chowdhury G, Dostalek M, Hsu E, Nguyen LP, Bradfield CA and Guengerich FP. Structural identification of diindole Ah receptor agonists derived from degradation of indole-3-pyruvic acid. Chem. Res. Toxicol. 2009, 22, 1905-1912.
Chowdhury G, and Guengerich FP. Tandem Mass Spectrometry-based Detection of C4?-Oxidized Abasic Sites at Specific Positions in DNA Fragments. Chem. Res. Toxicol. 2009, 22, 1310-1319.
Chowdhury G, and Guengerich FP. Direct detection and mapping of sites of modifications in DNA by tandem mass spectrometry. Angew. Chem. Int. Ed. 2008, 47, 381-384.
Chowdhury G, Junnutula V, Daniels JS, Greenberg MM and Gates KS. DNA strand damage product analysis provides evidence that the tumor cell-specific cytotoxin tirapazamine produces hydroxyl radical and acts as a surrogate for O2. J. Am. Chem. Soc. 2007, 129, 12870-12877
National and International Recognition
First Prize, oral presentation, Division of Chemical Toxicology, 238th American Chemical Society National Meeting, Washington DC, (2009).
First Prize, oral presentation, Division of Chemical Toxicology, 232nd American Chemical Society National Meeting, San Francisco, CA (2006).
Breckenridge/Lyons award for outstanding graduate research; Department of Chemistry, University of Missouri-Columbia (2003).
Dr. Chowdhury did his PhD from Dr. Kent Gates' lab at University of Missouri-Columbia. He did his postdoc in Dr. F. Peter Guengerich's lab, a world renowned lab in the field of cytochrome P450 and molecular toxicology. He worked as a research instructor at the Vanderbilt University Medical Center before joining Covance Laboratories Inc. in Madison, WI, USA as a staff Scientist. During his career he has published more than 30 papers in international journals.
Dr. Chowdhury specializes in molecular toxicology and drug metabolism. His research spans from the study of DNA and protein damage to P450, drug metabolism and mass spectrometry. At present he is interested in understanding the mechanism of toxicity of thalidomide and reactive intermediates formed from various drugs. He is also a reviewer for Chemical research in Toxicology.