Synergistic increase in chromosomal breakage within the euchromatin induced by an interaction of the benzene metabolites phenol and hydroquinone in mice.

The hematopoietic and carcinogenic effects of benzene may result from an interaction of various benzene metabolites. Following the co-administration of phenol and hydroquinone, a synergistic increase in myelotoxicity and genotoxicity has been observed in the bone marrow of mice. To understand the mechanisms underlying these synergistic genotoxic effects we have studied the origin of micronuclei (MN) formed in bone marrow erythrocytes following the co-administration of these two metabolites. Phenol and hydroquinone were administered to male CD-1 mice by i.p. injection three times at 24 h intervals. The frequency of MN was evaluated in bone marrow cells harvested 24 h following the final dose. A marked increase in MN was observed in mice co-administered phenol and hydroquinone, which was significantly greater than that observed with the individual metabolites. Labeling with the CREST antibody and multicolor fluorescence in situ hybridization with the mouse major and minor satellite probes indicated that both chromosomal loss and breakage and occurred. The major increase in MN induced by the phenol and hydroquinone combination originated from breakage in the euchromatic region of the mouse chromosomes. The origin of MN in mice co-administered phenol and hydroquinone differed substantially from that induced by hydroquinone alone, but was almost identical to that seen in MN from benzene-treated mice. These results strongly support the hypothesis that interactive effects among benzene metabolites play an important role in the genotoxic and carcinogenic effects of benzene.