Graduate Thesis Or Dissertation
 

Hepatotoxicity of monochlorobenzene in rats and rainbow trout

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  • The hepatotoxicity of CB was studied in the Sprague-Dawley rat and rainbow trout. In rats, an ip dosage of 9.8 mmol/kg CB (~̲ LD10) produced evidence of liver toxicity over a 72 hr time course. Sulfobromophthalein (BSP) retention maximized 3-16 hr post treatment and normalized after 72 hr whereas plasma alanine aminotransferase activity (ALT) and morphological evidence of damage maximized about 48 hr after dosing. Maximum covalent binding to liver protein (3.07 nmol/mg) had occurred by 24 hr and approximately 36% of the administered dose had appeared in the urine by 48 hr. In contrast to the rat, trout were relatively refractory to liver necrosis. Covalent binding in trout was approximately one-fourth that seen in the rat over a similar time course, and less than one percent of a given dose of CB was excreted in the urine. Rat liver and plasma CB concentrations were proportionally increased over the dosage range of 2.0-14.7 mmol/kg, but marked centrolobular necrosis and rat elevations were seen only at the highest dosages (9.8 and 14.7 mmol/kg). Liver concentration of CB in the rat was two and one-half times that seen in the trout. All doses of CB depressed glutathione (GSH) to between 30 and 40% of control rats by four hr. GSH levels remained depressed through eight hr after 9.8 or 14.7 mmol/kg. Trout GSH was depressed only 20% by a dosage of 9.8 mmol/kg and the recovery to control GSH levels was much slower than in the rat. Control levels of GSH in the rat liver were about three times that in the trout. Both species were equally susceptible to GSH depletion by diethyl maleate (DEM). In rats, covalent binding was dose related up to 9.8 mmol/kg. The highest dosage of CB had binding equal to the 4.9 mmol/kg dosage. This decrease in binding was not due to P450 depression or necrotic liver cells. Pretreatment studies with phenobarbital (Pb), β- naphthoflavone (BNF), and DEM indicated that there was no correlation between covalent binding or GSH content and liver necrosis in either trout or rats. The relative refractoriness of trout to liver necrosis was apparently not due to less absorption or metabolism of the toxicant. The necrosis seen in each species appears to be associated with a P450 isozyme that is inducible by Pb, but not BNF; thus, indicating that the type of CB metabolite may be important in the liver toxicity.
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