Skip Navigation


ToxSci Advance Access originally published online on February 22, 2006
Toxicological Sciences 2006 91(1):42-48; doi:10.1093/toxsci/kfj139
This Article
Right arrow Full Text Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
91/1/42    most recent
kfj139v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
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 Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Han, J.-F.
Right arrow Articles by Hong, J.-Y.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Han, J.-F.
Right arrow Articles by Hong, J.-Y.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Effect of Genetic Variation on Human Cytochrome P450 Reductase-Mediated Paraquat Cytotoxicity

Jing-Fen Han, Shou-Lin Wang, Xiao-Yang He, Chun-Yong Liu and Jun-Yan Hong1

School of Public Health/Environmental and Occupational Health Sciences Institute, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey 08854

Received December 23, 2005; accepted February 3, 2006

Paraquat (1,1'-dimethyl-4,4'-bipyridylium dichloride) is a widely used herbicide and is highly toxic to human and animals. The mechanisms of paraquat toxicity involve the generation of superoxide anion through the process of redox cycling. NADPH-cytochrome P450 oxidoreductase (POR) has been reported to be a major enzyme for one-electron reduction of paraquat that initiates the redox cycling. Recently, a total of six missense variants of human POR have been identified in patients with discorded steroidogenesis. However, the effect of these genetic variations on POR-mediated paraquat toxicity is not known. Using the Flp-In Chinese hamster ovary (CHO) cells stably expressing either mouse or human POR and the cells with POR knockdown by siRNA, we confirmed that POR is responsible for paraquat-induced cytotoxicity. We further used this validated system to compare paraquat-induced toxicity among the cells that stably expressed wild-type human POR and its natural variants. While there was no difference in paraquat-induced toxicity between the cells expressing wild-type human POR and the Cys569Tyr variant, the toxicity in cells expressing all the other variants (Tyr181Asp, Ala287Pro, Arg457His, Val492Glu, and Val608Phe) was significantly decreased. Our results provide further evidence on the important role of POR in paraquat-induced toxicity and suggest that individuals carrying the functional variant POR alleles may have an altered susceptibility to paraquat exposure.

Key Words: NADPH-cytochrome POR; paraquat; genetic variants; Flp-In CHO cells; siRNA knockdown.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
J. Belik, M. Jerkic, B. A. S. McIntyre, J. Pan, J. Leen, L. X. Yu, R. M. Henkelman, M. Toporsian, and M. Letarte
Age-dependent endothelial nitric oxide synthase uncoupling in pulmonary arteries of endoglin heterozygous mice
Am J Physiol Lung Cell Mol Physiol, December 1, 2009; 297(6): L1170 - L1178.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
Y. Gu, A. V. Patterson, G. J. Atwell, S. B. Chernikova, J. M. Brown, L. H. Thompson, and W. R. Wilson
Roles of DNA repair and reductase activity in the cytotoxicity of the hypoxia-activated dinitrobenzamide mustard PR-104A
Mol. Cancer Ther., June 1, 2009; 8(6): 1714 - 1723.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
J.-F. Han, X.-Y. He, J. S. Herrington, L. A. White, J.-F. Zhang, and J.-Y. Hong
Metabolism of 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) by Human CYP1B1 Genetic Variants
Drug Metab. Dispos., April 1, 2008; 36(4): 745 - 752.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
J. P. Gray, D. E. Heck, V. Mishin, P. J. S. Smith, J.-Y. Hong, M. Thiruchelvam, D. A. Cory-Slechta, D. L. Laskin, and J. D. Laskin
Paraquat Increases Cyanide-insensitive Respiration in Murine Lung Epithelial Cells by Activating an NAD(P)H:Paraquat Oxidoreductase: IDENTIFICATION OF THE ENZYME AS THIOREDOXIN REDUCTASE
J. Biol. Chem., March 16, 2007; 282(11): 7939 - 7949.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
S.-L. Wang, J.-F. Han, X.-Y. He, X.-R. Wang, and J.-Y. Hong
Genetic Variation of Human Cytochrome P450 Reductase as a Potential Biomarker for Mitomycin C-Induced Cytotoxicity
Drug Metab. Dispos., January 1, 2007; 35(1): 176 - 179.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.