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Comparative metabolism and toxicity of dichlorobenzenes in Sprague-Dawley, Fischer-344 and human liver slices

University of Arizona, Departments of Pharmacology and, Pharmacology and Toxicology, Tucson, Arizona, USA

Steven J Hasal

University of Arizona, Departments of Pharmacology and, Pharmacology and Toxicology, Tucson, Arizona, USA

I Glenn Sipes

University of Arizona, Departments of Pharmacology and, Pharmacology and Toxicology, Tucson, Arizona, USA

A Jay Gandolfi

University of Arizona, Departments of Pharmacology and, Pharmacology and Toxicology, Tucson, Arizona, USA

Klaus Brendel

University of Arizona, Departments of Pharmacology and, Pharmacology and Toxicology, Tucson, Arizona, USA

1 Precision-cut liver slices, prepared from Sprague- Dawley and Fischer-344 rats and donated human liver tis sue, were used to identify differences in 1,2-dichloroben zene (1,2-DCB), 1,3-dichlorobenzene (1,3-DCB) and 1,4- dichlorobenzene (1,4-DCB) metabolism and how it may relate to toxicity.

2 Rat and human liver slices were incubated with 1 mM of either dichlorobenzene to determine metabolism and toxi city, at 2 and 6 h of organ culture.

3 The human liver slices metabolised the dichloroben zenes to a greater extent than those from either of the rat strains. Liver slices from the Fischer-344 strain had a higher metabolic rate than the slices from the Sprague- Dawley rat strain.

4 The metabolic rate of dichlorobenzene isomers did not consistently correlate with its toxicity. For example, human slices did not exhibit any hepatotoxicity, even though they metabolised these compounds to a greater extent than either rat strain.

5 Cross species covalent binding did not correlate with toxicity endpoints measured in this study.

6 The phase two metabolite profiles for each of the iso mers in human and rat slices were similar in that the glu tathione-cysteine conjugate was the major metabolite.

7 The use of an in vitro system which utilises human liver slices might provide an important bridge between animal derived data and the human situation.

Key Words: metabolism • hepatotoxicity • human liver slices • rat liver slices • dichlorobenzenes

Human & Experimental Toxicology, Vol. 14, No. 5, 414-421 (1995)
DOI: 10.1177/096032719501400505


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