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THE DIFFERENTIAL HEPATOTOXICITY AND CYTOCHROME P450 RESPONSE OF F344 RATS TO THE THREE ISOMERS OF DICHLOROBENZENE
Citation:
Allis, J., J. Simmons, D. House, B. Robinson, AND F. Berman. THE DIFFERENTIAL HEPATOTOXICITY AND CYTOCHROME P450 RESPONSE OF F344 RATS TO THE THREE ISOMERS OF DICHLOROBENZENE. U.S. Environmental Protection Agency, Washington, D.C., EPA/600/J-93/102 (NTIS PB93175719).
Description:
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 toxic thresholds and to further e1ucidate the role of cytochrome P450 in the metabolism and toxicity of these compounds. In a novel study design employing one animal per dose level, Fischer-344 rats were gavaged with up to 25 different dosages, then evaluated 24 hr later. Hepatic necrosis, serum alanine amino-transferase and serum aspartate aminotrans-ferase exhibited similar patterns demonstrating that o-DCB was the most toxic in terms of both threshold and degree of response at dosages above threshold. For these three endpoints m-DCB exhibited a lesser toxicity. p-DCB was not hepatotoxic as judged by the same endpoints, but hepatic degenerative changes were found. Total hepatic cytochrome P450 (P450) responses were also different after treatment with each isomer. o-DCB produced a dose-dependent decrease in P450 beginning at dosages lower than the hepatotoxic threshold and appears to be a suicide substrate for P450. m-DCB treatment increased P450 at dosages below the threshold for toxicity 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 have led to a proposed explanation of literature data and increased understanding of the metabolism and toxicity of the dichlorobenzenes in rats.