The acute hepatotoxicity of the isomers of dichlorobenzene in Fischer-344 and Sprague-Dawley rats: isomer-specific and strain-specific differential toxicity.
The acute hepatotoxicity of the three isomers of dichlorobenzene (DCB) was evaluated in male Fischer-344 (F344) rats at various times following ip administration. Plasma alanine aminotransferase (ALT) activity, measured in F344 rats 24 hr postexposure, was dramatically elevated following doses of 1.8-5.4 mmol/kg of o-DCB. Conversely, equimolar doses of p-DCB produced no such toxicity, while m-DCB produced intermediate hepatic injury at or above doses of 2.7 mmol/kg. Histopathological changes in livers from treated animals qualitatively reflected elevations in 24-hr plasma ALT activity (time to maximal elevation). Phenobarbital pretreatment potentiated the acute hepatotoxicity of o- and m-DCB, but did not affect the toxicity of p-DCB. Likewise, SKF-525A pretreatment inhibited the hepatotoxicity of o-DCB. Equimolar doses of o- and m-DCB produced approximately equivalent depletion of intrahepatic glutathione, while p-DCB had no effect on hepatic GSH. Furthermore, prior depletion of hepatic glutathione by pretreatment with phorone markedly potentiated the hepatotoxicity of o- and m-DCB, while increasing the toxicity of p-DCB to a far lesser degree. The differential hepatotoxicity of the o- and m-DCB does not appear to be explained adequately by differences in their hepatic distribution or in vivo covalent binding to hepatic proteins. Interestingly, male Sprague-Dawley (SD) rats are relatively refractive to the acute hepatotoxicity of o-DCB following ip administration of 1.8 and 5.4 mmol/kg. The combination of these dramatic differences (structure-activity and animal strains) should be useful in elucidating key events involved in the hepatotoxicity caused by these compounds.
Stine
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Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson 85721.
Gunawardhana
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Sipes
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D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D002722:Chlorobenzenes / Q000378:metabolism / Q000633:toxicity*; D004347:Drug Interactions; D007274:Injections, Intraperitoneal; D007536:Isomerism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D011919:Rats, Inbred Strains; D013045:Species Specificity
D002722:Chlorobenzenes; D011725:Pyridines; C013109:metapyrone; C004726:2-dichlorobenzene; C042146:1,3-dichlorobenzene; C018511:4-dichlorobenzene; D000410:Alanine Transaminase