JBC

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Belcourt, M. F.
Right arrow Articles by Sartorelli, A. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Belcourt, M. F.
Right arrow Articles by Sartorelli, A. C.

J Biol Chem, Vol. 273, Issue 15, 8875-8881, April 10, 1998

The Intracellular Location of NADH:Cytochrome b5 Reductase Modulates the Cytotoxicity of the Mitomycins to Chinese Hamster Ovary Cells

Michael F. BelcourtDagger , William F. HodnickDagger , Sara RockwellDagger §, and Alan C. SartorelliDagger

From the Departments of Dagger  Pharmacology and § Therapeutic Radiology and Developmental Therapeutics Program, Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut 06520

NADH:cytochrome b5 reductase activates the mitomycins to alkylating intermediates in vitro. To investigate the intracellular role of this enzyme in mitomycin bioactivation, Chinese hamster ovary cell transfectants overexpressing rat NADH:cytochrome b5 reductase were generated. An NADH:cytochrome b5 reductase-transfected clone expressed 9-fold more enzyme than did parental cells; the levels of other mitomycin-activating oxidoreductases were unchanged. Although this enzyme activates the mitomycins in vitro, its overexpression in living cells caused decreases in sensitivity to mitomycin C in air and decreases in sensitivity to porfiromycin under both air and hypoxia. Mitomycin C cytotoxicity under hypoxia was similar to parental cells. Because NADH:cytochrome b5 reductase resides predominantly in the mitochondria of these cells, this enzyme may sequester these drugs in this compartment, thereby decreasing nuclear DNA alkylations and reducing cytotoxicity. A cytosolic form of NADH:cytochrome b5 reductase was generated. Transfectants expressing the cytosolic enzyme were restored to parental line sensitivity to both mitomycin C and porfiromycin in air with marked increases in drug sensitivity under hypoxia. The results implicate NADH:cytochrome b5 reductase in the differential bioactivation of the mitomycins and indicate that the subcellular site of drug activation can have complex effects on drug cytotoxicity.

Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.


This article has been cited by other articles:


Home page
 Proc. Natl. Acad. Sci. USAHome page
H. A. Seow, P. G. Penketh, K. Shyam, S. Rockwell, and A. C. Sartorelli

PNAS, June 28, 2005; 102(26): 9282 - 9287.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
T. H. Ward, S. Danson, A. T. McGown, M. Ranson, N. A. Coe, G. C. Jayson, J. Cummings, R. H.J. Hargreaves, and J. Butler
Preclinical Evaluation of the Pharmacodynamic Properties of 2,5-Diaziridinyl-3-Hydroxymethyl-6-Methyl-1,4-Benzoquinone
Clin. Cancer Res., April 1, 2005; 11(7): 2695 - 2701.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
H. A. Seow, M. F. Belcourt, P. G. Penketh, W. F. Hodnick, M. Tomasz, S. Rockwell, and A. C. Sartorelli
Nuclear Localization of NADPH:Cytochrome c (P450) Reductase Enhances the Cytotoxicity of Mitomycin C to Chinese Hamster Ovary Cells
Mol. Pharmacol., February 1, 2005; 67(2): 417 - 423.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
H. A. Seow, P. G. Penketh, M. F. Belcourt, M. Tomasz, S. Rockwell, and A. C. Sartorelli
Nuclear Overexpression of NAD(P)H:Quinone Oxidoreductase 1 in Chinese Hamster Ovary Cells Increases the Cytotoxicity of Mitomycin C under Aerobic and Hypoxic Conditions
J. Biol. Chem., July 23, 2004; 279(30): 31606 - 31612.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
K. M. Holtz, S. Rockwell, M. Tomasz, and A. C. Sartorelli
Nuclear Overexpression of NADH:Cytochrome b5 Reductase Activity Increases the Cytotoxicity of Mitomycin C (MC) and the Total Number of MC-DNA Adducts in Chinese Hamster Ovary Cells
J. Biol. Chem., February 7, 2003; 278(7): 5029 - 5034.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
M. F. Belcourt, P. G. Penketh, W. F. Hodnick, D. A. Johnson, D. H. Sherman, S. Rockwell, and A. C. Sartorelli
Mitomycin resistance in mammalian cells expressing the bacterial mitomycin C resistance protein MCRA
PNAS, August 31, 1999; 96(18): 10489 - 10494.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
P. G. Penketh, W. F. Hodnick, M. F. Belcourt, K. Shyam, D. H. Sherman, and A. C. Sartorelli
Inhibition of DNA Cross-linking by Mitomycin C by Peroxidase-mediated Oxidation of Mitomycin C Hydroquinone
J. Biol. Chem., September 7, 2001; 276(37): 34445 - 34452.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
 All ASBMB Journals   Molecular and Cellular Proteomics 
 Journal of Lipid Research   ASBMB Today 
Copyright © 1998 by the American Society for Biochemistry and Molecular Biology.