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Abstract
While benzene is widely recognized as a human and animal carcinogen, the key mechanisms
underlying its carcinogenic effects remain unknown. Inhibition of topoisomerase II
(topoII) by benzene and its metabolites represents a potential mechanism by which
benzene could induce its chromosome-altering and leukemogenic effects. Previous work
from our laboratory and others has demonstrated that bioactive benzene metabolites
are capable of inhibiting topoII in isolated enzyme and cell culture systems. Similarly,
a decrease in topoII activity has been seen in the bone marrow of mice administered
benzene in vivo. The objective of these studies was to further investigate the mechanisms
by which the bioactivated benzene metabolite, hydroquinone (BAHQ), inhibits topoII
in vitro, and to identify the point(s) in the enzyme's catalytic cycle where inhibition
occurs. Our experiments indicate that BAHQ inhibits topoII at the DNA binding stage
as well as in the closed clamp stage in the catalytic cycle, thereby interfering with
either the binding to, or the release of, DNA from the enzyme. While increases in
the cleavable complex were also seen with BAHQ treatment, our results suggest that
this is related to a shift in equilibrium due to an accumulation of the topoII enzyme
at the closed clamp stage rather than a major inhibitory effect on the religation
step. An increase in cleavable complex formation as well as the inhibition of enzymatic
activity at the closed clamp and other stages of the catalytic cycle in bone marrow
cells would likely result in DNA breakage, the formation of chromosomal aberrations,
and could potentially result in leukemia-associated chromosomal translocations, similar
to those seen in leukemias induced by the bisdioxopiperazine type of catalytic topoII
inhibitors.