INHIBITION OF HUMAN TOPOISOMERASE-II IN-VITRO BY BIOACTIVE BENZENE METABOLITES

Benzene is a clastogenic and carcinogenic agent that induces acute mye logenous leukemia in humans and multiple types of tumors in animals. P revious research has indicated that benzene must first be metabolized to one or more bioactive species to exert its myelotoxic and genotoxic effects. To better understand the possible role of individual benzene metabolites in the leukemogenic process, as well as to further invest igate inhibition of topoisomerase II by benzene metabolites, a series of known and putative benzene metabolites, phenol, 4,4'-biphenol, 2,2' -biphenol, hydroquinone, catechol, 1,2,4-benzenetriol, 1,4-benzoquinon e, and trans-trans-muconaldehyde were tested for inhibitory effects in vitro on the human topoisomerase II enzyme. With minor modifications of the standard assay conditions, 1,4-benzoquinone and trans-trans-muc onaldehyde were shown to be directly inhibitory, whereas all of the ph enolic metabolites lites were shown to inhibit enzymatic activity foll owing bioactivation using a peroxidase activation system. The majority of compounds tested inhibited topoisomerase ii at concentrations at o r below 10 mu M. These results confirm and expand upon previous findin gs from our laboratory and indicate that many of the metabolites of be nzene could potentially interfere with topoisomerase II. Since other i nhibitors of topoisomerase II have been shown to induce leukemia in hu mans, inhibition of this enzyme by benzene metabolites may also play a role in the carcinogenic effects of benzene.