The differential hepatotoxicity and cytochrome P450 responses of Fischer-344 rats to the three isomers of dichlorobenzene.
The acute hepatotoxicity and response of hepatic cytochrome P450 to treatment with the three isomers of dichlorobenzene (DCB) have been investigated. The objectives were to estimate the onset of toxicity and to further elucidate the role of cytochrome P450 in the metabolism and toxicity of these compounds. In a study design employing one animal per dose level, Fischer-344 rats were gavaged with up to 25 different dosages, then evaluated 24 h later. Hepatic necrosis, serum alanine aminotransferase, and serum aspartate aminotransferase exhibited similar patterns demonstrating that ortho-DCB (o-DCB) was the most toxic in terms of both earliest onset and degree of response at higher dosages. For these three endpoints, meta-DCB (m-DCB) exhibited a lesser toxicity. Para-DCB (p-DCB) did not cause changes in these three endpoints, but hepatic degenerative changes were found. Total hepatic cytochrome P450 responses were also different after treatment with each isomer. The o-DCB produced a dose-dependent decrease in P450 beginning at dosages lower than the onset of necrosis and appeared to be a suicide substrate for P450. The m-DCB treatment increased P450 at dosages below the onset of necrosis and decreased P450 at higher dosages, with the decline preceding the onset of hepatocyte death. Treatment with p-DCB increased P450 beginning at 380 mg/kg. The combination of toxicity and P450 profiles has provided a framework for interpreting literature data on the metabolism and toxicity of the DCBs in rats. It is also noteworthy that o-DCB and p-DCB were administered at dosages several times the oral rat LD-50 (RTECS) without any lethality.
Allis
J W
JW
Health Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, N.C. 27711.
Simmons
J E
JE
House
D E
DE
Robinson
B L
BL
Berman
E
E
D000410:Alanine Transaminase / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D001219:Aspartate Aminotransferases / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury; D002722:Chlorobenzenes / Q000633:toxicity*; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D007536:Isomerism; D008107:Liver Diseases / Q000201:enzymology / Q000473:pathology; D008297:Male; D009336:Necrosis / Q000139:chemically induced; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344
D002722:Chlorobenzenes; D003577:Cytochrome P-450 Enzyme System; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase