Mechanisms for modification of bromobenzene hepatotoxicity by coadministered toluene and chlorobenzene

Abstract

Hepatotoxicity of bromobenzene (2 mmole/kg) in combination with toluene or chlorobenzene (4 mmole/kg each) were studied in vivo on the basis of GPT elevation and histological examinations. Both toluene and chlorobenzene suppressed bromobenzene hepatotoxicity 24 hr after the treatment, and chlorobenzene dramatically potentiated the toxicity at 48 hr. The glutathione level became lower at 12 hr and recovered at 24 hr when bromobenzene was given alone. The recovery delayed until 48 hr when chlorobenzene was coadministered. In experiments in vitro with microsomes from phenobarbital-pretreated rats, both toluene and chlorobenzene at 0.6 mM inhibited p-bromophenol formation noncompetitively but had no effect on o-isomer formation. Multiple factors may determine overall hepatotoxicity in combined exposure; bromobenzene hepatotoxicity will be suppressed in the early phase owing to metabolic inhibition of 3,4-epoxidation, but potentiated later because of delayed recovery in the glutathione level. A time-saving yet reliable assay system with an ECD-gas chromatograph was developed for bromobenzene metabolism study.