PRINCIPLES OF TOXICOLOGY

4.10 BONE MARROW SUPPRESSION AND LEUKEMIAS AND LYMPHOMAS 103
phenicol is an important antibiotic used to combat strains of bacteria that are resistant to first-line
antibiotics; however, it bears a well-recognized risk of bone marrow suppression. The drug phenylbutazone,
once commonly used as an antiinflammatory agent for treating arthritic conditions, is now
conservatively prescribed for only a few weeks at a time in order to reduce the chance of developing
bone marrow suppression.
The marrow suppressive effects of benzene were described long before benzene was established
as a cause of acute myelogenous leukemia (AML). Benzene’s suppressant effects range from mild and
reversible to lethal, namely, life-threatening aplastic anemia or pancytopenia. Preleukemia or
myelodysplasia, often viewed as a precursor to leukemia, is characterized by abnormal morphology
of blood cells and may be associated with chronic bone marrow suppression. Evidence of benzeneinduced
bone marrow suppression in humans is based on many studies. One of the most highly
publicized cases involved the Ohio Pliofilm workers of the 1940s and 1950s. The Pliofilm worker
studies provided evidence that benzene exposures exceeding 50–75 ppm were associated with
reductions in white blood cell counts. More recent evidence, using more sophisticated cell counting
methods, suggest that lymphocytes may be the most sensitive target of benzene .
Metabolite(s) of benzene is (are) the actual cause(s) of marrow suppression. Benzene is metabolized
by hepatic cytochrome P450 mixed function oxidases. Benzene is a substrate of cytochrome P450 IIE,
which is one of the many isozymes among the family of cytochrome P450 mixed-function oxidases.
Benzene oxide, the first intermediate in CYP 2EI-mediated metabolism, is converted into a number of
metabolites including phenol, hydroquinone, and muconic acid/muconaldehyde (see Figure 4.5). Two
benzene metabolites not shown in Figure 4.5 include catechol and trihydroxy benzene. In the bone
marrow, myeloperoxidase further oxidizes phenolic metabolites of benzene to form free radicals
capable of damaging the bone marrow.
Figure 4.5 Benzene’s Metabolism. Benzene is both bioactivated and detoxified via a number of different
enzymatic-mediated steps. The bioactivated metabolites of benzene, such as hydroquinone and muconaldehyde,
disrupt the various stages of blood formation in the bone marrow gives rise to any number of blood dyscrasias,
myelodyplastic syndrome, and acute myelogenous leukemia.