Potentiation of acute acetaminophen lethality by selenium and vitamin E deficiency in mice.
The effects of selenium, vitamin E, and DL-methionine deficiency on the acute lethality and hepatotoxicity of acetaminophen in male CD-1 mice were studied. Vitamin E and selenium deficiencies led to an increase in the acute lethality of acetaminophen, with a decrease in the LD50 from 376 to 84 mg/kg. These dietary deficiencies impaired the inducibility of the hepatic microsomal mixed function oxidase system by phenobarbital, but on the basis of the covalent binding of acetaminophen to microsomes, these treatments did not alter the activation of acetaminophen to a reactive intermediate by this system. Addition of methionine to the deficient diet restored hepatic glutathione content to control levels but did little to protect against the acute lethality of acetaminophen. In methionine-supplemented animals, the addition of either selenium or vitamin E increased the LD50 of acetaminophen to 167 and 200 mg/kg, respectively. Administration of a sublethal, toxic dose of acetaminophen (LD30) to the methionine-supplemented and selenium- and vitamin E-deficient mice did not produce any hepatic damage as evidenced by a lack of plasma aminotransferase elevation. In view of the known antioxidant effects of vitamin E and selenium, these data suggest the involvement of a reactive radical in the acute lethality of acetaminophen and further suggest that death from acute acetaminophen overdose in chronic selenium- and vitamin E-deficient mice may be unrelated to liver necrosis.
Peterson
F J
FJ
Research Service, Veterans Administration Medical Center, Minneapolis, MN 55417.
Lindemann
N J
NJ
Duquette
P H
PH
Holtzman
J L
JL
D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D001835:Body Weight; D004357:Drug Synergism; D007928:Lethal Dose 50; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008715:Methionine / Q000172:deficiency; D051379:Mice; D006899:Mixed Function Oxygenases / Q000378:metabolism; D012643:Selenium / Q000172:deficiency*; D014811:Vitamin E Deficiency / Q000378:metabolism*
D000082:Acetaminophen; D008715:Methionine; D006899:Mixed Function Oxygenases; D012643:Selenium