Dose and route dependency of metabolism and toxicity of chloroform in ethanol-treated rats.
The effects of a single dose of ethanol on the metabolism and toxicity of chloroform administered to rats per os (p.o.), intraperitoneally (i.p.), or by inhalation (inh) at different doses were investigated. Rats that had been given either ethanol (2 g/kg) or vehicle (water) alone at 4 p.m. on the previous day were challenged with chloroform at 10 a.m. p.o. (0.01, 0.2, or 0.4 g/kg), i.p. (0, 0.1, 0.2, or 0.4 g/kg), or inh (for 6 h each at 0, 50, 100, or 500 ppm). The ethanol treatment, which had no influence on the intake of food and water, increased chloroform metabolism in vitro about 1.5-fold with no significant influence on liver glutathione content. The treatment had a dose-dependent effect on the metabolism and toxicity of chloroform, and the effect differed depending on the route of administration. Compared at the same dose level, the area under the curve (AUC) of blood chloroform concentration was invariably smaller following p.o. than i.p. administration. In accordance with this, chloroform administered p.o. caused more deleterious hepatic damage than the same amount of chloroform administered i.p. Although ethanol treatment had no significant influence on the AUC at any dose by any route of administration, the toxicity of p.o.-administered chloroform was significantly higher in ethanol-treated rats than in control rats at a dose as low as 0.1 g/kg, whereas no significant difference was observed in toxicity between both groups of rats at such a low dose administered i.p.(ABSTRACT TRUNCATED AT 250 WORDS)
Wang
P Y
PY
Department of Environmental Health, Medical University of Yamanashi, Japan.
Kaneko
T
T
Tsukada
H
H
Sato
A
A
D000280:Administration, Inhalation; D000284:Administration, Oral; D000818:Animals; D002725:Chloroform / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004326:Drinking / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D000431:Ethanol / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism*; D007274:Injections, Intraperitoneal; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D051381:Rats; D017208:Rats, Wistar
D000431:Ethanol; D002725:Chloroform; D003577:Cytochrome P-450 Enzyme System; D005978:Glutathione