Metabolism of dichlorobenzenes in organ cultured liver slices.
A novel in vitro system was used to evaluate tissue specific toxicity. This system utilizes precision cut organ slices in dynamic organ culture and is viable for up to 24 hrs. The three isomers of dichlorobenzene were added to liver slices prepared from Sprague Dawley rats or human donors. The precursor dichlorobenzenes were radiolabelled and metabolites were separated by classes (i.e. glucuronides, sulfates and glutathione and cysteine conjugates). Covalent Binding of the dichlorobenzenes was also determined after extensive extraction of the tissue. The total amount of metabolism of the dichlorobenzenes varied depending on the isomer and the type of tissue. For example, the Sprague-Dawley rat liver slices metabolized 1,2-DCB and 1,3-DCB at approximately the same rate while 1,4-DCB was metabolized at a slower rate. This metabolism profile was also seen in the majority of the adult human liver slices. However, the fetal human slices showed that 1,4-DCB was metabolized to a greater extent than 1,3-DCB or 1,2-DCB while 1,3-DCB was metabolized at a faster rate than 1,2-DCB. Our results show that liver slices in organ culture are a suitable system for species comparisons and of structure/activity relationships in xenobiotic metabolism with an emphasis on the fate of reactive intermediates. In addition, this system is suitable for evaluation of hepatotoxic potency.
Fisher
R
R
Department of Pharmacology, University of Arizona, Tucson 85724.
McCarthy
S
S
Sipes
I G
IG
Hanzlik
R P
RP
Brendel
K
K
D000818:Animals; D002722:Chlorobenzenes / Q000378:metabolism*; D003545:Cysteine / Q000378:metabolism; D005333:Fetus / Q000378:metabolism; D005965:Glucuronates / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007536:Isomerism; D008099:Liver / Q000378:metabolism*; D009924:Organ Culture Techniques; D051381:Rats; D011919:Rats, Inbred Strains; D013431:Sulfates / Q000378:metabolism
D002722:Chlorobenzenes; D005965:Glucuronates; D013431:Sulfates; C004726:2-dichlorobenzene; C042146:1,3-dichlorobenzene; C018511:4-dichlorobenzene; D005978:Glutathione; D003545:Cysteine