Comparative metabolism and toxicity of dichlorobenzenes in Sprague-Dawley, Fischer-344 and human liver slices.
1. Precision-cut liver slices, prepared from Sprague-Dawley and Fischer-344 rats and donated human liver tissue, were used to identify differences in 1,2-dichlorobenzene (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 toxicity, at 2 and 6 h of organ culture. 3. The human liver slices metabolised the dichlorobenzenes 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 hepatoxicity, 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 isomers in human and rat slices were similar in that the glutathione-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.
Fisher
R L
RL
University of Arizona, Department of Pharmacology, Tucson 85724, USA.
Hasal
S J
SJ
Sipes
I G
IG
Gandolfi
A J
AJ
Brendel
K
K
D000293:Adolescent; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D002722:Chlorobenzenes / Q000378:metabolism* / Q000633:toxicity*; D003545:Cysteine / Q000378:metabolism; D005965:Glucuronates / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D011188:Potassium / Q000032:analysis; D014176:Protein Biosynthesis; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013429:Sulfatases / Q000378:metabolism
D002722:Chlorobenzenes; D005965:Glucuronates; D013429:Sulfatases; D003545:Cysteine; D011188:Potassium