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The Role of Protein-Protein and Protein-Membrane Interactions on P450 Function
EE. Scott, CR. Wolf, M. Otyepka, SC. Humphreys, JR. Reed, CJ. Henderson, LA. McLaughlin, M. Paloncýová, V. Navrátilová, K. Berka, P. Anzenbacher, UP. Dahal, C. Barnaba, JA. Brozik, JP. Jones, DF. Estrada, JS. Laurence, JW. Park, WL. Backes,
Drug metabolism and disposition.
2016 ;
44 (4) :
576-90.
[pub] 20160205
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články, Research Support, N.I.H., Extramural, práce podpořená grantem, přehledy
Perzistentní odkaz
https://www.medvik.cz/link/bmc17000520
PubMed
26851242
DOI
10.1124/dmd.115.068569
Knihovny.cz E-zdroje
- MeSH
- buněčná membrána metabolismus MeSH
- endoplazmatické retikulum metabolismus MeSH
- interakční proteinové domény a motivy fyziologie MeSH
- jaterní mikrozomy metabolismus MeSH
- lidé MeSH
- sekundární struktura proteinů MeSH
- systém (enzymů) cytochromů P-450 chemie fyziologie MeSH
- výzkumná zpráva * MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Research Support, N.I.H., Extramural MeSH
This symposium summary, sponsored by the ASPET, was held at Experimental Biology 2015 on March 29, 2015, in Boston, Massachusetts. The symposium focused on: 1) the interactions of cytochrome P450s (P450s) with their redox partners; and 2) the role of the lipid membrane in their orientation and stabilization. Two presentations discussed the interactions of P450s with NADPH-P450 reductase (CPR) and cytochrome b5. First, solution nuclear magnetic resonance was used to compare the protein interactions that facilitated either the hydroxylase or lyase activities of CYP17A1. The lyase interaction was stimulated by the presence of b5 and 17α-hydroxypregnenolone, whereas the hydroxylase reaction was predominant in the absence of b5. The role of b5 was also shown in vivo by selective hepatic knockout of b5 from mice expressing CYP3A4 and CYP2D6; the lack of b5 caused a decrease in the clearance of several substrates. The role of the membrane on P450 orientation was examined using computational methods, showing that the proximal region of the P450 molecule faced the aqueous phase. The distal region, containing the substrate-access channel, was associated with the membrane. The interaction of NADPH-P450 reductase (CPR) with the membrane was also described, showing the ability of CPR to "helicopter" above the membrane. Finally, the endoplasmic reticulum (ER) was shown to be heterogeneous, having ordered membrane regions containing cholesterol and more disordered regions. Interestingly, two closely related P450s, CYP1A1 and CYP1A2, resided in different regions of the ER. The structural characteristics of their localization were examined. These studies emphasize the importance of P450 protein organization to their function.
Citace poskytuje Crossref.org
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- $a Scott, Emily E $u Departments of Medicinal Chemistry and Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas (D.F.E, J.S.L., E.E.S.); Division of Cancer Research, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, United Kingdom (C.R.W., C.J.H., L.A.M.); Regional Center of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science (M.O., M.P., V.N., K.B.) and Department of Pharmacology, Faculty of Medicine and Dentistry (P.A.), Palacký University, Olomouc, Czech Republic; Department of Chemistry, Washington State University, Pullman, Washington (S.C.H., U.P.D., C.B., J.A.B., J.P.J.); and Department of Pharmacology and Experimental Therapeutics, and the Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana (J.R.R., J.W.P., W.L.B.).
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- $a The Role of Protein-Protein and Protein-Membrane Interactions on P450 Function / $c EE. Scott, CR. Wolf, M. Otyepka, SC. Humphreys, JR. Reed, CJ. Henderson, LA. McLaughlin, M. Paloncýová, V. Navrátilová, K. Berka, P. Anzenbacher, UP. Dahal, C. Barnaba, JA. Brozik, JP. Jones, DF. Estrada, JS. Laurence, JW. Park, WL. Backes,
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- $a This symposium summary, sponsored by the ASPET, was held at Experimental Biology 2015 on March 29, 2015, in Boston, Massachusetts. The symposium focused on: 1) the interactions of cytochrome P450s (P450s) with their redox partners; and 2) the role of the lipid membrane in their orientation and stabilization. Two presentations discussed the interactions of P450s with NADPH-P450 reductase (CPR) and cytochrome b5. First, solution nuclear magnetic resonance was used to compare the protein interactions that facilitated either the hydroxylase or lyase activities of CYP17A1. The lyase interaction was stimulated by the presence of b5 and 17α-hydroxypregnenolone, whereas the hydroxylase reaction was predominant in the absence of b5. The role of b5 was also shown in vivo by selective hepatic knockout of b5 from mice expressing CYP3A4 and CYP2D6; the lack of b5 caused a decrease in the clearance of several substrates. The role of the membrane on P450 orientation was examined using computational methods, showing that the proximal region of the P450 molecule faced the aqueous phase. The distal region, containing the substrate-access channel, was associated with the membrane. The interaction of NADPH-P450 reductase (CPR) with the membrane was also described, showing the ability of CPR to "helicopter" above the membrane. Finally, the endoplasmic reticulum (ER) was shown to be heterogeneous, having ordered membrane regions containing cholesterol and more disordered regions. Interestingly, two closely related P450s, CYP1A1 and CYP1A2, resided in different regions of the ER. The structural characteristics of their localization were examined. These studies emphasize the importance of P450 protein organization to their function.
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- $a Wolf, C Roland $u Departments of Medicinal Chemistry and Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas (D.F.E, J.S.L., E.E.S.); Division of Cancer Research, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, United Kingdom (C.R.W., C.J.H., L.A.M.); Regional Center of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science (M.O., M.P., V.N., K.B.) and Department of Pharmacology, Faculty of Medicine and Dentistry (P.A.), Palacký University, Olomouc, Czech Republic; Department of Chemistry, Washington State University, Pullman, Washington (S.C.H., U.P.D., C.B., J.A.B., J.P.J.); and Department of Pharmacology and Experimental Therapeutics, and the Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana (J.R.R., J.W.P., W.L.B.).
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- $a Otyepka, Michal $u Departments of Medicinal Chemistry and Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas (D.F.E, J.S.L., E.E.S.); Division of Cancer Research, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, United Kingdom (C.R.W., C.J.H., L.A.M.); Regional Center of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science (M.O., M.P., V.N., K.B.) and Department of Pharmacology, Faculty of Medicine and Dentistry (P.A.), Palacký University, Olomouc, Czech Republic; Department of Chemistry, Washington State University, Pullman, Washington (S.C.H., U.P.D., C.B., J.A.B., J.P.J.); and Department of Pharmacology and Experimental Therapeutics, and the Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana (J.R.R., J.W.P., W.L.B.).
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- $a Humphreys, Sara C $u Departments of Medicinal Chemistry and Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas (D.F.E, J.S.L., E.E.S.); Division of Cancer Research, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, United Kingdom (C.R.W., C.J.H., L.A.M.); Regional Center of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science (M.O., M.P., V.N., K.B.) and Department of Pharmacology, Faculty of Medicine and Dentistry (P.A.), Palacký University, Olomouc, Czech Republic; Department of Chemistry, Washington State University, Pullman, Washington (S.C.H., U.P.D., C.B., J.A.B., J.P.J.); and Department of Pharmacology and Experimental Therapeutics, and the Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana (J.R.R., J.W.P., W.L.B.).
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- $a Reed, James R $u Departments of Medicinal Chemistry and Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas (D.F.E, J.S.L., E.E.S.); Division of Cancer Research, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, United Kingdom (C.R.W., C.J.H., L.A.M.); Regional Center of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science (M.O., M.P., V.N., K.B.) and Department of Pharmacology, Faculty of Medicine and Dentistry (P.A.), Palacký University, Olomouc, Czech Republic; Department of Chemistry, Washington State University, Pullman, Washington (S.C.H., U.P.D., C.B., J.A.B., J.P.J.); and Department of Pharmacology and Experimental Therapeutics, and the Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana (J.R.R., J.W.P., W.L.B.).
- 700 1_
- $a Henderson, Colin J $u Departments of Medicinal Chemistry and Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas (D.F.E, J.S.L., E.E.S.); Division of Cancer Research, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, United Kingdom (C.R.W., C.J.H., L.A.M.); Regional Center of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science (M.O., M.P., V.N., K.B.) and Department of Pharmacology, Faculty of Medicine and Dentistry (P.A.), Palacký University, Olomouc, Czech Republic; Department of Chemistry, Washington State University, Pullman, Washington (S.C.H., U.P.D., C.B., J.A.B., J.P.J.); and Department of Pharmacology and Experimental Therapeutics, and the Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana (J.R.R., J.W.P., W.L.B.).
- 700 1_
- $a McLaughlin, Lesley A $u Departments of Medicinal Chemistry and Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas (D.F.E, J.S.L., E.E.S.); Division of Cancer Research, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, United Kingdom (C.R.W., C.J.H., L.A.M.); Regional Center of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science (M.O., M.P., V.N., K.B.) and Department of Pharmacology, Faculty of Medicine and Dentistry (P.A.), Palacký University, Olomouc, Czech Republic; Department of Chemistry, Washington State University, Pullman, Washington (S.C.H., U.P.D., C.B., J.A.B., J.P.J.); and Department of Pharmacology and Experimental Therapeutics, and the Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana (J.R.R., J.W.P., W.L.B.).
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- $a Paloncýová, Markéta $u Departments of Medicinal Chemistry and Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas (D.F.E, J.S.L., E.E.S.); Division of Cancer Research, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, United Kingdom (C.R.W., C.J.H., L.A.M.); Regional Center of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science (M.O., M.P., V.N., K.B.) and Department of Pharmacology, Faculty of Medicine and Dentistry (P.A.), Palacký University, Olomouc, Czech Republic; Department of Chemistry, Washington State University, Pullman, Washington (S.C.H., U.P.D., C.B., J.A.B., J.P.J.); and Department of Pharmacology and Experimental Therapeutics, and the Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana (J.R.R., J.W.P., W.L.B.).
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- $a Navrátilová, Veronika $u Departments of Medicinal Chemistry and Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas (D.F.E, J.S.L., E.E.S.); Division of Cancer Research, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, United Kingdom (C.R.W., C.J.H., L.A.M.); Regional Center of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science (M.O., M.P., V.N., K.B.) and Department of Pharmacology, Faculty of Medicine and Dentistry (P.A.), Palacký University, Olomouc, Czech Republic; Department of Chemistry, Washington State University, Pullman, Washington (S.C.H., U.P.D., C.B., J.A.B., J.P.J.); and Department of Pharmacology and Experimental Therapeutics, and the Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana (J.R.R., J.W.P., W.L.B.).
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- $a Berka, Karel $u Departments of Medicinal Chemistry and Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas (D.F.E, J.S.L., E.E.S.); Division of Cancer Research, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, United Kingdom (C.R.W., C.J.H., L.A.M.); Regional Center of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science (M.O., M.P., V.N., K.B.) and Department of Pharmacology, Faculty of Medicine and Dentistry (P.A.), Palacký University, Olomouc, Czech Republic; Department of Chemistry, Washington State University, Pullman, Washington (S.C.H., U.P.D., C.B., J.A.B., J.P.J.); and Department of Pharmacology and Experimental Therapeutics, and the Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana (J.R.R., J.W.P., W.L.B.).
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- $a Anzenbacher, Pavel $u Departments of Medicinal Chemistry and Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas (D.F.E, J.S.L., E.E.S.); Division of Cancer Research, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, United Kingdom (C.R.W., C.J.H., L.A.M.); Regional Center of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science (M.O., M.P., V.N., K.B.) and Department of Pharmacology, Faculty of Medicine and Dentistry (P.A.), Palacký University, Olomouc, Czech Republic; Department of Chemistry, Washington State University, Pullman, Washington (S.C.H., U.P.D., C.B., J.A.B., J.P.J.); and Department of Pharmacology and Experimental Therapeutics, and the Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana (J.R.R., J.W.P., W.L.B.). $7 xx0034447 $4
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- $a Dahal, Upendra P $u Departments of Medicinal Chemistry and Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas (D.F.E, J.S.L., E.E.S.); Division of Cancer Research, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, United Kingdom (C.R.W., C.J.H., L.A.M.); Regional Center of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science (M.O., M.P., V.N., K.B.) and Department of Pharmacology, Faculty of Medicine and Dentistry (P.A.), Palacký University, Olomouc, Czech Republic; Department of Chemistry, Washington State University, Pullman, Washington (S.C.H., U.P.D., C.B., J.A.B., J.P.J.); and Department of Pharmacology and Experimental Therapeutics, and the Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana (J.R.R., J.W.P., W.L.B.).
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- $a Barnaba, Carlo $u Departments of Medicinal Chemistry and Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas (D.F.E, J.S.L., E.E.S.); Division of Cancer Research, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, United Kingdom (C.R.W., C.J.H., L.A.M.); Regional Center of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science (M.O., M.P., V.N., K.B.) and Department of Pharmacology, Faculty of Medicine and Dentistry (P.A.), Palacký University, Olomouc, Czech Republic; Department of Chemistry, Washington State University, Pullman, Washington (S.C.H., U.P.D., C.B., J.A.B., J.P.J.); and Department of Pharmacology and Experimental Therapeutics, and the Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana (J.R.R., J.W.P., W.L.B.).
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- $a Brozik, James A $u Departments of Medicinal Chemistry and Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas (D.F.E, J.S.L., E.E.S.); Division of Cancer Research, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, United Kingdom (C.R.W., C.J.H., L.A.M.); Regional Center of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science (M.O., M.P., V.N., K.B.) and Department of Pharmacology, Faculty of Medicine and Dentistry (P.A.), Palacký University, Olomouc, Czech Republic; Department of Chemistry, Washington State University, Pullman, Washington (S.C.H., U.P.D., C.B., J.A.B., J.P.J.); and Department of Pharmacology and Experimental Therapeutics, and the Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana (J.R.R., J.W.P., W.L.B.).
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- $a Jones, Jeffrey P $u Departments of Medicinal Chemistry and Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas (D.F.E, J.S.L., E.E.S.); Division of Cancer Research, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, United Kingdom (C.R.W., C.J.H., L.A.M.); Regional Center of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science (M.O., M.P., V.N., K.B.) and Department of Pharmacology, Faculty of Medicine and Dentistry (P.A.), Palacký University, Olomouc, Czech Republic; Department of Chemistry, Washington State University, Pullman, Washington (S.C.H., U.P.D., C.B., J.A.B., J.P.J.); and Department of Pharmacology and Experimental Therapeutics, and the Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana (J.R.R., J.W.P., W.L.B.).
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- $a Estrada, D Fernando $u Departments of Medicinal Chemistry and Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas (D.F.E, J.S.L., E.E.S.); Division of Cancer Research, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, United Kingdom (C.R.W., C.J.H., L.A.M.); Regional Center of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science (M.O., M.P., V.N., K.B.) and Department of Pharmacology, Faculty of Medicine and Dentistry (P.A.), Palacký University, Olomouc, Czech Republic; Department of Chemistry, Washington State University, Pullman, Washington (S.C.H., U.P.D., C.B., J.A.B., J.P.J.); and Department of Pharmacology and Experimental Therapeutics, and the Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana (J.R.R., J.W.P., W.L.B.).
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- $a Laurence, Jennifer S $u Departments of Medicinal Chemistry and Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas (D.F.E, J.S.L., E.E.S.); Division of Cancer Research, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, United Kingdom (C.R.W., C.J.H., L.A.M.); Regional Center of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science (M.O., M.P., V.N., K.B.) and Department of Pharmacology, Faculty of Medicine and Dentistry (P.A.), Palacký University, Olomouc, Czech Republic; Department of Chemistry, Washington State University, Pullman, Washington (S.C.H., U.P.D., C.B., J.A.B., J.P.J.); and Department of Pharmacology and Experimental Therapeutics, and the Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana (J.R.R., J.W.P., W.L.B.).
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- $a Park, Ji Won $u Departments of Medicinal Chemistry and Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas (D.F.E, J.S.L., E.E.S.); Division of Cancer Research, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, United Kingdom (C.R.W., C.J.H., L.A.M.); Regional Center of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science (M.O., M.P., V.N., K.B.) and Department of Pharmacology, Faculty of Medicine and Dentistry (P.A.), Palacký University, Olomouc, Czech Republic; Department of Chemistry, Washington State University, Pullman, Washington (S.C.H., U.P.D., C.B., J.A.B., J.P.J.); and Department of Pharmacology and Experimental Therapeutics, and the Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana (J.R.R., J.W.P., W.L.B.).
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- $a Backes, Wayne L $u Departments of Medicinal Chemistry and Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas (D.F.E, J.S.L., E.E.S.); Division of Cancer Research, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, United Kingdom (C.R.W., C.J.H., L.A.M.); Regional Center of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science (M.O., M.P., V.N., K.B.) and Department of Pharmacology, Faculty of Medicine and Dentistry (P.A.), Palacký University, Olomouc, Czech Republic; Department of Chemistry, Washington State University, Pullman, Washington (S.C.H., U.P.D., C.B., J.A.B., J.P.J.); and Department of Pharmacology and Experimental Therapeutics, and the Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana (J.R.R., J.W.P., W.L.B.) wbacke@lsuhsc.edu.
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