© 1995 Oxford University Press
other |
Topoisomerase inhibition by phenolic metabolites: a potential mechanism for benzene's clastogenic effects
Environmental Toxicology Graduate Program, Department of Entomology, University of California Riverside, California 92521, USA
2To whom correspondence should be addressed
Exposure to benzene, a human and animal carcinogen, results in the formation of structural chromosomal aberrations in the bone marrow and blood cells of animals and humans. The mechanisms underlying these clastogenic effects are unknown. Inhibition of enzymes involved in DNA replication and repair, such as topoisomerase enzymes, by the metabolites of benzene represents a potential mechanism for the formation of chromosomal aberrations. To test this hypothesis, the inhibitory effects of various phenolic and qulnone metabolites of benzene on the activity of human topoisomerases I and II were studied in vitro. No inhibition of topolsomerase I was seen with any of the tested metabolites. Inhibitory effects on topoisomerase II were not observed for hydroqulnone, phenol, 2,2'-biphenol, 4,4'-biphenol and catechol at concentrations as high as 500 µM. 1,4-Benzoquinone and 1,2,4-benzenetrlol inhibited topoisomerase II at relatively high 500 and 250 µM concentrations, respectively. However following bioactlvation using a peroxldase/H2O2 system, Inhibitory effects were seen at concentrations as low as 50 µM for both phenol and 2,2'-biphenol and 10 µM for 4,4'-biphenol. The addition of reduced glutathione (GSH) to the 4,4'-biphenol and horseradish peroxidase reaction system protected topoiso merase II from inhibition suggesting that diphenoquinone or another oxidation product formed from 4,4'-biphenol might be the reactive species. These in vitro results indicate that inhibition of topolsomerase II may contribute to the clastogenic and carcinogenic effects of benzene. In addition, metabolites formed from these phenolic compounds appear to represent several new types of topolsomerase II-Inhibiting compounds.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  Y. MURAKAMI, H. ISHII, S. HOSHINA, N. TAKADA, A. UEKI, S. TANAKA, Y. KADOMA, S. ITO, M. MACHINO, and S. FUJISAWA Antioxidant and Cyclooxygenase-2-inhibiting Activity of 4,4'-Biphenol, 2,2'-Biphenol and Phenol Anticancer Res, June 1, 2009; 29(6): 2403 - 2410. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S Wilbur, D Wohlers, S Paikoff, L. Keith, and O Faroon ATSDR evaluation of health effects of benzene and relevance to public health Toxicology and Industrial Health, June 1, 2008; 24(5-6): 263 - 398. [Abstract] [PDF]
|
|
|
|
 |
|
 M. T. Smith, Y. Wang, C. F. Skibola, D. J. Slater, L. L. Nigro, P. C. Nowell, B. J. Lange, and C. A. Felix Low NAD(P)H:quinone oxidoreductase activity is associated with increased risk of leukemia with MLL translocations in infants and children Blood, December 15, 2002; 100(13): 4590 - 4593. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. J. Raffini, D. J. Slater, E. F. Rappaport, L. Lo Nigro, N.-K. V. Cheung, J. A. Biegel, P. C. Nowell, B. J. Lange, and C. A. Felix Panhandle and reverse-panhandle PCR enable cloning of der(11) and der(other) genomic breakpoint junctions of MLL translocations and identify complex translocation of MLL, AF-4, and CDK6 PNAS, April 2, 2002; 99(7): 4568 - 4573. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Marcon, A. Zijno, G. Dobrowolny, A. Carere, and R. Crebelli Detection of 1cen-1q12 lesions in different phases of the cell cycle: dual colour FISH analysis of peripheral lymphocytes from subjects with occupational exposure to petroleum fuels Mutagenesis, March 1, 2002; 17(2): 157 - 162. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. K. Baker, E. U. Kurz, D. W. Pyatt, R. D. Irons, and D. J. Kroll Benzene metabolites antagonize etoposide-stabilized cleavable complexes of DNA topoisomerase II{alpha} Blood, August 1, 2001; 98(3): 830 - 833. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. Wiemels, A. Pagnamenta, G. M. Taylor, O. B. Eden, F. E. Alexander, and M. F. Greaves A Lack of a Functional NAD(P)H:Quinone Oxidoreductase Allele Is Selectively Associated with Pediatric Leukemias That Have MLL Fusions Cancer Res., August 1, 1999; 59(16): 4095 - 4099. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. L. Gist and J. R. Burg Benzene--a Review of the Literature from a Health Effects Perspective Toxicology and Industrial Health, November 1, 1997; 13(6): 661 - 714. [Abstract] [PDF]
|
|
|
|
|
|
R. H. Schiestl, J. Aubrecht, F. Khogali, and N. Carls Carcinogens induce reversion of the mouse pink-eyed unstable mutation PNAS, April 29, 1997; 94(9): 4576 - 4581. [Abstract] [Full Text] [PDF]
|
|