Benzene inhibits RNA synthesis in mitochondria from liver and bone marrow

Abstract

Mitochondria, isolated from livers of partially hepatectomized rats given a single dose of benzene (2200 mg/kg) 10 h post-hepatectomy, show inhibition of RNA synthesis when they are incubated in vitro. In addition benzene inhibits the synthesis of all three types of RNA in 24-h regenerating rat liver mitochondria in vitro and also in normal rabbit liver mitochondria. Similarly benzene caused a dose-dependent inhibition of RNA synthesis in vitro in mitoplasts derived from cat and rabbit bone marrow mitochondria. The inhibition of mitochondrial RNA synthesis by benzene in all these systems shows a requirement for exogenous NADPH which suggests that benzene must be bioactivated within the organelle. Equivalent concentrations of toluene show no inhibition and the concomitant addition of equimolar toluene and benzene results in protection against benzene inhibition. Similar results were obtained with either intact mitochondria or mitoplasts, mitochondria stripped of their outer membrane. These results suggest that inhibition by benzene is not merely the result of solvent effects on the membranes and that the bioactivation of benzene occurs within the organelle and not by contaminating microsomes adventitiously bound to the outer mitochondrial membrane. Both liver and bone marrow mitochondria incubated with [ 3H]benzene appear to activate the benzene to a metabolite which can covalently bind to guanine residues in their DNA. Benzene can also inhibit mitochondrial translation most probably because an inhibition of transcription results in a lack of mRNA and a subsequent disaggregation of polysomes. These results demonstrate that mitochondria can bioactivate benzene to a toxic metabolite which binds to DNA and results in an inability of mitochondrial RNA polymerase to transcribe the genome which subsequently result in an inhibition of translation.