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.