The differential hepatotoxicity and cytochrome P450 responses of fischer‐344 rats to the three isomers of dichlorobenzene

Abstract

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.

Thirteen‐week Inhalation Toxicity of p‐Dichlorobenzene in Mice and Rats

“…Hissink et al 20) reported that total in vitro conversion of p-DCB into covalently bound, reactive metabolites by liver microsomes was in the descending order of mouse> rat, and that reactive metabolites such a s 2 , 5 -d i c h l o r o h y d r o q u i n o n e a n d 2 , 5 -dichlorobenzoquinone were produced more in mice than in rats. Allis et al 36) showed that the severity of hepatotoxicity induced by o-, m-and p-DCB was in the descending order of o-> m-> p-DCB, and was closely associated with the rank order of the hepatic P-450 responses to these three isomers. Therefore, it can be inferred from these results that the large species difference in hepatotoxicity seen in this study is attributable to a difference in the metabolic capacity of p-DCB of the liver P-450 between rats and mice.…”

“…The ingested p-DCB goes through the liver during the first pass after the gastro-intestinal absorption, whereas the inhaled p-DCB is absorbed into the lung, distributed through the bloodstream to various organs, including the liver and adipose tissue. Since the absorption rate of p-DCB was comparable for the lung (33%) 38) and for the gastro-intestinal tract (55 %) 40) , and since the covalently bound, reactive metabolites were reported to be responsible for the hepatoxicity 20,36) , it is likely that the first pass effect by the oral intake enhances p-DCBinduced hepatotoxicity compared to inhalation exposure.…”

A Comparative Human Health Risk Assessment ofp-Dichlorobenzene-Based Toilet Rimblock Products Versus Fragrance/Surfactant-Based Alternatives

“…Acute liver damage, as assessed by histopathology and serum enzyme/biochemical indicators following gavage exposure, was not induced by high levels of p-dichlorobenzene in rat given single doses of ≤2790 mg/kg (Allis et al, 1992), rats and mice given single doses of ≤1200 mg/kg/d (Eldridge et al, 1992), or rats and mice administered ≤300 and ≤600 mg/kg/day, respectively, 5 d/week for 1 week (Lake et al, 1997). Porphyria, manifested as markedly elevated porphyrin levels in the liver and urine and suggestive of hepatic damage, was reported in rats that were orally exposed to 770 mg/kg/d for 5 d (Rimington & Ziegler, 1963).…”

Comparison of the Hepatic and Renal Effects of 1,4-Dichlorobenzene in the Rat and Mouse

“…Human hepatic cytochrome P450 isoenzymes which can metabolize DCB to 2,5-dichlorophenol include CYP1A2 and CYP2E1 (Bogaards et al, 1995). Studies into the acute toxicity of DCB and its isomers have demonstrated that 1,2-dichlorobenzene is more toxic to rat and mouse liver and to rat kidney than 1,3-dichlorobenzene and DCB (Allis et al, 1992;Valentovic et al, 1993;Umemura et al, 1996).DCB is considered to be a nongenotoxic agent as demonstrated by results of a number of short-term tests for mutagenic and genotoxic potential (Loeser and Litchfield, 1983; NTP, 1987;Steinmetz et al, 1988). The carcinogenicity of DCB has been evaluated in a 2-year study in F344 rats and B6C3F, mice (NTP, 1987).…”

“…Human hepatic cytochrome P450 isoenzymes which can metabolize DCB to 2,5-dichlorophenol include CYP1A2 and CYP2E1 (Bogaards et al, 1995). Studies into the acute toxicity of DCB and its isomers have demonstrated that 1,2-dichlorobenzene is more toxic to rat and mouse liver and to rat kidney than 1,3-dichlorobenzene and DCB (Allis et al, 1992;Valentovic et al, 1993;Umemura et al, 1996).…”