TOPOISOMERASE INHIBITION BY PHENOLIC METABOLITES - A POTENTIAL MECHANISM FOR BENZENES CLASTOGENIC EFFECTS

Exposure to benzene, a human and animal carcinogen, results in the for mation of structural chromosomal aberrations in the bone marrow and bl ood cells of animals and humans. The mechanisms underlying these clast ogenic effects are unknown. Inhibition of enzymes involved in DNA repl ication and repair, such as topoisomerase enzymes, by the metabolites of benzene represents a potential mechanism for the formation of chrom osomal aberrations. To test this hypothesis, the inhibitory effects of various phenolic and quinone metabolites of benzene on the activity o f human topoisomerases I and II were studied in vitro. No inhibition o f topoisomerase I was seen with any of the tested metabolites. Inhibit ory effects on topoisomerase II were not observed for hydroquinone, ph enol, 2,2'-biphenol, 4,4'-biphenol and catechol at concentrations as h igh as 500 mu M 1,4-Benzoquinone and 1,2,4-benzenetriol inhibited topo isomerase II at relatively high 500 and 250 mu M concentrations, respe ctively. However following bioactivation using a peroxidase/H2O2 syste m, inhibitory effects were seen at concentrations as low as 50 mu M fo r both phenol and 2,2'-biphenol and 10 mu M for 4,4'-biphenol. The add ition of reduced glutathione (GSH) to the 4,4'-biphenol and horseradis h peroxidase reaction system protected topoisomerase II from inhibitio n suggesting that diphenoquinone or another oxidation product formed f rom 4,4'-biphenol might be the reactive species. These in vitro result s indicate that inhibition of topoisomerase II may contribute to the c lastogenic and carcinogenic effects of benzene. In addition, metabolit es formed from these phenolic compounds appear to represent several ne w types of topoisomerase II-inhibiting compounds.