The hepatotoxicity of the isomers of dichlorobenzene: Structure-toxicity relationships and interactions with carbon tetrachloride
AuthorStine, Eric Randal.
AdvisorSipes, I. G.
MetadataShow full item record
PublisherThe University of Arizona.
RightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
AbstractThe three isomers of dichlorobenzene (DCB) exhibit marked differences in hepatotoxicity following intraperitoneal (ip) administration in male F-344 rats. Plasma GPT activity, measured 24 hours post exposure, was elevated to approximately 4080 units/ml following a 1.8 mmol/kg dose of o-DCB. Conversely, n-DCB produced only a moderate elevation (306 units/ml) following a 4.5 mmol/kg dose, while p-DCB produced no elevation in GPT activity at this dose (24 units/ml). Ultra-structurally, o- and m-DCB induced elevations in GPT activity were associated with a centrilobular pattern of hepatic necrosis. The role of cytochrome P-450 mediated bioactivation in DCB-induced hepatotoxicity was demonstrated by elevated GPT activities following an otherwise nontoxic 0.9 mmol/kg dose of either o- or m-DCB in phenobarbital pretreated animals (16770 and 21540 units/ml, respectively). The paraisomer of DCB showed no induction of toxicity with phenobarbital pretreatment. Hepatic glutathione (GSH) concentrations were reduced 0.5, 3 and 5 hours after a 1.8 mmol/kg dose of either o- or m-DCB, a dose which produces hepatotoxicity only for o-DCB. Pretreatment of animals with phorone depleted hepatic GSH to 15% of control levels within two hours; subsequent ip administration of either o- or m-DCB (1.8 mmol/kg) produced approximately equivalent elevations in GPT activity for both isomers (5749 ± 648 and 4732 ± 857 units/ml, respectively). In vitro incubations of o- and m-DCB with GSH and rat liver cytosolic fraction, suggested that GSH may bind m-DCB without prior bioactivation, thereby reducing the hepatotoxicity of this isomer relative to the more toxic ortho isomer. The interactive hepatotoxicity of the dichlorobenzenes with carbon tetrachloride (CCl₄) was also investigated. Concomitant ip injection of CCl₄ (1.0 mmol/kg) and o-DCB (2.7 mmol/kg) produced a marked inhibition of o-DCB hepatotoxicity, as measured by GPT activity (approximately 200 units/ml vs. 7450 units/ml for o-DCB alone). The mechanism of this inhibition of o-DCB hepatotoxicity was shown to be a reduction in the cytochrome P-450 mediated bioactivation of o-DCB, by CCl₄. A similar inhibition of o-DCB hepatotoxicity was seen following administration of CCl₄ as a pretreatment, via the drinking water. Concomitant ip administration of CCl₄ with either m- or p-DCB also produced a reduction in the metabolism of the dichlorobenzene.
Degree ProgramPharmacology & Toxicology