Effects of inhibition of ornithine aminotransferase on thioacetamide-induced hepatogenic encephalopathy.
Repeated administration of thioacetamide (TAA) to CD1 mice produced hepatic failure and biochemical and behavioral effects characteristic of hepatogenic encephalopathy (HE). The symptoms in mice resembled those previously observed in rats after similar treatments. It is, however, obvious that both in rats and mice the severity of symptoms depends not only on dose and dosing schedule of TAA, but also on strain and body weight (age). Administration of 5-fluoromethylornithine (5FMOrn), a selective inactivator of ornithine aminotransferase (OAT), significantly reduced mortality, and it ameliorated most of the TAA-induced pathologic symptoms, such as hypothermia, decreased locomotor and exploratory behavior, pathologic liver function and amino acid patterns. The most prominent biochemical consequence of 5FMOrn administration is the elevation of ornithine concentrations in tissues, including the brain, and in body fluids. Elevated ornithine concentrations are, therefore, the most likely basis for the therapeutic effects of 5FMOrn. In agreement with this notion is the enhancement of citrulline and urea formation. These findings and the observation that administration of ornithine in combination with a branched-chain 2-oxoacid ameliorated the pathologic symptoms of portal-systemic encephalopathy suggest inhibition of OAT in the treatment of this disease. The liver protective effect of 5FMOrn is not yet understood; the enhancement of regenerative processes is a likely explanation.
Sarhan
S
S
Marion Merrell Dow Research Institute, Strasbourg, France.
Knödgen
B
B
Grauffel
C
C
Seiler
N
N
D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism; D002956:Citrulline / Q000378:metabolism; D006501:Hepatic Encephalopathy / Q000139:chemically induced* / Q000188:drug therapy / Q000503:physiopathology; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D009043:Motor Activity; D009952:Ornithine / Q000031:analogs & derivatives / Q000378:metabolism / Q000627:therapeutic use; D009953:Ornithine-Oxo-Acid Transaminase / Q000037:antagonists & inhibitors*; D013853:Thioacetamide; D014508:Urea / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D000596:Amino Acids; D013853:Thioacetamide; C057405:5-fluoromethylornithine; D002956:Citrulline; D005680:gamma-Aminobutyric Acid; D014508:Urea; D009952:Ornithine; D009953:Ornithine-Oxo-Acid Transaminase