Ethanol feeding stimulates trichloromethyl radical formation from carbon tetrachloride in liver.
1. Female, Sprague-Dawley rats were fed liquid ethanol or control diets, both of which contained fat either at 35% (high fat, HF) or 12% (low fat, LF) of total calories. The rats were given an oral dose of 13CCl4 along with the spin trapping agent, phenyl tert.-butyl-nitrone (PBN). 2. Analysis of the hepatic lipid extracts revealed a signal due to the trichloromethyl radical (CCl3) adduct of PBN. Ethanol feeding in the HF diet increased the signal intensity two-fold over controls, whereas ethanol feeding in the LF diet caused only a 35% increase. 3. In isolated microsomes, ethanol feeding in HF or LF diets increased CCl3 formation by approx. 8-fold and 4-fold, respectively, over control values. These data support the hypothesis that ethanol induces a cytochrome P-450 isozyme that is highly active in the metabolism of CCl4 to the CCl3 radical. 4. Ethanol feeding markedly enhanced the hepatotoxicity of CCl4; however, there were no differences in the loss of hepatic enzymes into blood between the ethanol plus HF or ethanol plus LF groups. Thus, ethanol is likely to increase CCl4 toxicity by some mechanism in addition to increased trichloromethyl radical formation.
Reinke
L A
LA
Department of Pharmacology, University of Oklahoma Health Sciences Center, Oklahoma City 73190.
Lai
E K
EK
McCay
P B
PB
D000818:Animals; D002251:Carbon Tetrachloride / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity*; D004041:Dietary Fats / Q000008:administration & dosage; D004357:Drug Synergism; D000431:Ethanol / Q000633:toxicity*; D005260:Female; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D004041:Dietary Fats; C025280:trichloromethyl free radical; D000431:Ethanol; D002251:Carbon Tetrachloride