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Grover Paul Miller, Ph.D.
Associate Professor
NIH postdoctoral fellow, Vanderbilt University, 1999-2001
Ph.D., Pennsylvania State University, 1997
B.S., Louisiana State University, 1992
Research Specialty:
My major area of interest is the study of individual reactions and ultimately
the pathways that contribute to the metabolism of xenobiotic compounds, such as
drugs, pollutants, and food additives. In particular, there is an emphasis on
the biochemistry of cytochrome P450s due to their dominant role on xenobiotic
metabolism. Several in vitro approaches are being used include site-directed
and random mutagenesis, kinetic analysis, and substrate-activity relationships.
As a complement to those efforts, we employ biophysical methods to assess the
function of protein interactions with P450 complex partners, substrate, and
membrane within the context of the P450 catalytic cycle. Because these enzymes
often comprise a single step with metabolic pathways, we are exploring the role
of coupling between P450s and other enzymes and the resulting impact on
metabolic efficiency. The long-term goal of our research is to identify the
factors that modulate metabolic activity toward xenobiotic compounds and
establish their relevance to biological outcomes such as drug response and
cancer.
Examples of current projects:
Improving warfarin anticoagulant therapy through metabolic pathway mapping and
metabolite profiling
Coumadin (R/S-warfarin)
is a commonly prescribed anticoagulant for over 20 million Americans for the
treatment of
atrial
fibrillation, mechanical heart valves, venous thromboembolism and other
coagulopathies. While highly efficacious, warfarin treatment is challenging due
to a narrow therapeutic range and high inter-individual variations in response.
A better understanding of the mechanisms underlying patient responses to
warfarin therapy remains an important goal in patient safety.
Inter-individual differences in response to warfarin have been attributed to
variations in drug metabolism.
Knowledge of the in vivo relevance of these metabolic pathways is incomplete.
We are addressing this gap of knowledge by determining metabolic pathways for
warfarin and the mechanisms underlying their clinical relevance in patients. As
a complement to those efforts, we are
establishing the predictive power of warfarin metabolite profiles to aid safe
and effective dosing for patients based on a single blood draw.
Metabolic
profiles reflect contributions from clinical factors, e.g. gender, age, body
weight, diet, disease, genetics, and concurrent medications. Therefore, they
represent the most accurate measure of phenotype variations in metabolism among
patients and a rich source of potentially useful clinical biomarkers. Achieving
these laudable goals requires a strong, diversified team of researchers; my
group's focus on the biochemistry of metabolism is balanced by expertise in
organic chemistry (Tom Goodwin, Hendrix College, metabolite standard syntheses),
analytical chemistry (Gunnar Boysen, UAMS, metabolite profiling by LC-MS), and
biostatistics (Ralph Kodell, UAMS, biomarker identification).
Determining the molecular basis for enantiospecific reactions by CYP2C9
The promise of green chemistry brings the benefits of chemistry without the
costs on the environment and thus sustainable development for our society. A
practical consequence of green chemistry is the incorporation of
biotechnological advances in agriculture,
medicine, industry, and environment. In particular, cytochrome P450s (CYP for
specific isoforms) have been utilized for bioremediation of pollutants,
biosensors, and the synthesis of specialty chemicals, drugs, and metabolites.
The expansion of these applications requires the ability to tailor-make
catalysts that generate new molecules of interest. The synthesis and analysis
of chiral molecules is a rapidly growing area in biotechnology. However, the
molecular basis for P450 selection of chiral molecules has not been adequately
investigated, and thus there exists a significant challenge to identify and/or
engineer enantiospecific P450s for reactions of interest. For this project, we
are investigating the molecular basis for CYP2C9 enantiospecificity toward
molecules through a multi-institutional collaborative project involving
computational (in silico) and biochemical (in vitro) approaches. These efforts
are possible through our collaboration with Martin Perry (Ouachita Baptist
University), who is directing our computational studies.
Selected publications
Jones, DR,
Miller, GP (2011) Assays and applications in warfarin metabolism: what we
know, how we know it, and what we need to know,
Expert Opin
Drug Metab Toxicol 7,
857-74. [Abstract]
Jones, DR,
Boysen, B, Miller, GP (2011) Novel Dual-Phase Ultra Performance Liquid
Chromatography-Tandem Mass Spectrometry Assay for Profiling Enantiomeric
Hydroxywarfarins and Warfarin in Human Plasma,
J Chromatogr B
879, 1056-62. [Abstract]
Miller, GP
(2010)
Warfarin
Therapy: How the less interesting half just got interesting,
J Thromb Haemost,8,
2705-7.
[Abstract]
Jones, DR, Kim,
S-Y; Guderyon, M, Yun, C-H, Moran, J, Miller, GP (2010) Hydroxywarfarin
Metabolites Potently Inhibit CYP2C9 Metabolism of S-Warfarin,
Chem Res Tox
23,
939-45. [Abstract]
Jones, DR, Kim,
S-Y, Boysen, G, Yun, C-H, Miller, GP (2010) Contribution of Three CYP3A
Isoforms to Metabolism of R- and S-Warfarin, Drug Metab Lett 4,
213-9. [Abstract]
Jones DR,
Moran JH, Miller GP (2010) Warfarin and UDP-glucuronosyltransferases:
writing a new chapter of metabolism. Drug Metab Rev 42, 55-61. [Abstract]
Miller, GP,
Jones, DR, Sullivan, SZ, Mazur, A, Owen, SN, Mitchell, N, Radominska-Pandya, A,
Moran, JH (2009) Assessing Cytochrome P450 and UDP-Glucuronosyltransferase
Contributions to Warfarin Metabolism in Humans. Chem Res Tox
22,
1239-45. [Abstract]
Jang, H-H,
Jamakhandi, AP, Sullivan, SZ, Yun, C-H, Hollenberg, PF, Miller, GP (2010)
Beta Sheet 2 - Alpha Helix C Loop of Cytochrome P450 Reductase Serves as a
Docking Site for Redox Partners, Biochem Biophys Acta - Proteins and
Proteomics, 1804, 1285-1293. [Abstract]
Mazur, A,
Lichti, CF, Prather, P, Zielinska, AK, Bratton, SM, Gallus-Zawada, A, Finel, M,
Miller, GP, Radominska-Pandya, A, Moran, JH (2009) Characterization of
Human Hepatic and Extrahepatic UDP-glucuronosyltransferase (UGTs) Enzymes
Involved in the Metabolism of Classical Cannabinoids.
Drug Metab
Dispo
37, 1496-504. PMC2698943 [Abstract]
Miller, GP
(2008) Advances in the Interpretation and Prediction of CYP2E1 Metabolism from a
Biochemical Perspective. Expert Opin Drug Metab Toxicol
4,
1053-64. [Abstract]
Zielinska, A,
Lichti, CF, Bratton, S, Mitchell, NC, Gallus-Zawada, A, Le, V-H, Finel, M,
Miller, GP, Radominska-Pandya, A, Moran, JH (2008) Glucuronidation of
Monohydroxylated Warfarin Metabolites by Human Liver Microsomes and Human
Recombinant UDP-Glucuronosyltransferases. J Pharmacol Exp Ther
324, 139-48. PMC2275122 [Abstract]
Collom, SL,
Laddusaw, RM, Kuzmic, P, Burch, AM, Perry, Jr, MD, Miller, GP (2008)
CYP2E1 Substrate Inhibition: Mechanistic interpretation through an effector site
for monocyclic compounds. J Biol Chem 283, 3487-96.
[Abstract]
Miller, GP,
Lichti, CF, Zielinska, AK, Mazur, A, Bratton, SM,
Gallus-Zawada, A, Finel, M, Moran, JH,
Radominska-Pandya, A (2008) Identification of Hydroxywarfarin Binding Site in
Human UGT1A10: Phenylalanine90 is crucial for the glucuronidation of 6- and
7-hydroxy- but not 8-hydroxywarfarin.
Drug Metab Dispo
36, 2211-8. [Abstract]
Collom, SL,
Jamakhandi, AP, Tackett, AJ, Radominska-Pandya, A and Miller, GP (2007)
CYP2E1 Active Site Residues in Substrate Recognition Sequence 5 Identified by
Photoaffinity Labeling and Homology Modeling.
Arch Biochem
Biophys 459,
59-69.
PMC1994253 [Abstract]
Jamakhandi, AP, Kuzmic, P, Sanders, DA, Miller, GP (2007) Global Analysis
of Protein-Protein Interactions Reveals Multiple CYP2E1-Reductase
Complexes. Biochemistry 46, 10192-201. PMC2592557 [Abstract]
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E-mail: |
MillerGroverP@uams.edu |
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Office: |
(501) 526-6486 |
Biomed B421A |
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Lab: |
(501)
526-6487 |
Biomed B420 |
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FAX: |
(501) 686-8169 |
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