Different change patterns of the isozymes of cytochrome P450 and glutathione S-transferases in chemically induced liver damage in rat.
In this experiment, we studied the different changes in activities and protein levels of each subform of hepatic cytochrome P450 and glutathione S-transferase (GST), in chemical-induced liver injury in rats. Rats were administered 1,1-dichloroethylene (DCE), allyl alcohol (AA), bromobenzene (BB) and N,N-dimethylformamide (DMF) p.o. once every two days for 7 times, and decapitated 18 hr after the last administration. DCE and AA showed stronger hepatic toxicity than BB and DMF, as serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were higher in DCE and AA treated rats than in BB and DMF groups. Anti-cytochrome P450 inhibitable activity of toluene metabolism and/or immunoblot analysis showed that CYP2E1 and CYP2B1/2 were induced by BB and DMF, but not by the other two chemicals; CYP2C11 was greatly decreased by all of the four toxicants; and CYP1A1/2 was slightly reduced by the four treatments. These changes were reflected in testosterone metabolism. Formation of 6 beta- and 7 alpha-hydroxytestosterone from testosterone was enhanced only in DMF-treated rats, whereas that of 2 alpha- and 16 alpha-hydroxytestosterone was reduced by all of the four chemicals. Serum GST activity was increased only in BB and DMF treated rats, but liver cytosolic GST activity was enhanced by all of the four hepatotoxicants, with higher values in BB and DMF groups than in DCE and AA groups. Immunoblot analysis demonstrated that GST Yp was induced by BB and DMF treatments, and Ya and Yc were increased only by BB. GST Yk and Yb1 were not affected by the treatments. The different change patterns of enzymes by a specific toxin and the similar modifying effect on a specific enzyme by different toxins were discussed in relation to the liver damage and to the heterogeneous distribution of enzymes in liver.
Wang
R S
RS
Division of Health Effects Research, National Institute of Industrial Health, Kawasaki, Japan.
Nakajima
T
T
Honma
T
T
D000284:Administration, Oral; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051381:Rats; D015262:Xenobiotics / Q000633:toxicity*
D007527:Isoenzymes; D015262:Xenobiotics; D003577:Cytochrome P-450 Enzyme System; D005982:Glutathione Transferase