Chemical models for toxic metabolites of bromobenzene derivatives. Relative toxicity toward isolated hepatocytes.

Abstract:

:In the rat the hepatotoxicity of bromobenzene is greatly enhanced by the introduction of a cyano group adjacent to the bromine (i.e. o-bromobenzonitrile). Epoxide metabolites of these aryl halides are believed to be the actual toxic species, but epoxides of the latter compound also possess a second site of chemical reactivity not found in epoxides of bromobenzene, i.e. a Michael acceptor group formally related to acrylonitrile. Because these epoxides have never been isolated or synthesized for direct evaluation of their toxicity we have determined the toxicity toward isolated rat hepatocytes of a series of cyclohexene and cyclohexadiene derivatives containing epoxide and/or alpha, beta-unsaturated nitrile functional groups. Simple epoxides and unsaturated nitriles were much less toxic than bromobenzene itself, even if both groups were present in the same molecule. However, alpha, beta-unsaturated epoxides were found to be 2-3 times more toxic than bromobenzene, and at least 10 times more toxic than their saturated analogs, which is consistent with their relatively greater chemical reactivity. It is unlikely that Michael acceptor metabolites account for the increased toxicity of o-bromobenzonitrile relative to bromobenzene.

journal_name

Toxicology

journal_title

Toxicology

authors

Gottschall DW,Harder RR,Wiley RA,Hanzlik RP

doi

10.1016/0300-483x(84)90106-9

subject

Has Abstract

pub_date

1984-06-01 00:00:00

pages

251-9

issue

3-4

eissn

0300-483X

issn

1879-3185

pii

0300-483X(84)90106-9

journal_volume

31

pub_type

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