PRINCIPLES OF TOXICOLOGY - Biology East Borneo

4.10 BONE MARROW SUPPRESSION AND LEUKEMIAS AND LYMPHOMAS 103phenicol is an important antibiotic used to combat strains of bacteria that are resistant to first-lineantibiotics; 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 nowconservatively prescribed for only a few weeks at a time in order to reduce the chance of developingbone marrow suppression.The marrow suppressive effects of benzene were described long before benzene was establishedas a cause of acute myelogenous leukemia (AML). Benzene’s suppressant effects range from mild andreversible to lethal, namely, life-threatening aplastic anemia or pancytopenia. Preleukemia ormyelodysplasia, often viewed as a precursor to leukemia, is characterized by abnormal morphologyof blood cells and may be associated with chronic bone marrow suppression. Evidence of benzeneinducedbone marrow suppression in humans is based on many studies. One of the most highlypublicized cases involved the Ohio Pliofilm workers of the 1940s and 1950s. The Pliofilm workerstudies provided evidence that benzene exposures exceeding 50–75 ppm were associated withreductions in white blood cell counts. More recent evidence, using more sophisticated cell countingmethods, 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 metabolizedby 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 ofmetabolites including phenol, hydroquinone, and muconic acid/muconaldehyde (see Figure 4.5). Twobenzene metabolites not shown in Figure 4.5 include catechol and trihydroxy benzene. In the bonemarrow, myeloperoxidase further oxidizes phenolic metabolites of benzene to form free radicalscapable of damaging the bone marrow.Figure 4.5 Benzene’s Metabolism. Benzene is both bioactivated and detoxified via a number of differentenzymatic-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.