Contrasting effects of thioacetamide-induced liver damage on the brain uptake indices of ornithine, arginine and lysine: modulation by treatment with ornithine aspartate.
The dibasic amino acids arginine (ARG), ornithine (ORN) and lysine (LYS) are transported by a common saturable transporter (system gamma +) at the blood-brain barrier (BBB). In the present study we compared the brain uptake index (BUI) for radiolabelled ORN, ARG and LYS in control rats and in rats treated with thioacetamide (TAA) to induce hepatic encephalopathy (HE). Some animals received i.v. ornithine aspartate (OA), a drug structurally related to the gamma + substrates that ameliorates neurological symptoms following liver damage by improving detoxification of ammonia in peripheral tissues: the compound was administered either by continuous infusion for 6h at a concentration of 2 g/kg (final blood concentration ranging from 0.19-0.5 mM), or as a 15 sec. bolus together with the radiolabelled amino acids, at a concentration of 0.35 mM. TAA treatment resulted in a delayed and progressive increase of BUI for ORN, to 186% of control at 7d post-treatment and to 345% of control at 21d post-treatment, when despite sustained liver damage, HE symptoms were already absent. In contrast, the BUI for ARG decreased to 30% of control at 7d post-treatment and remained low (42% of control) at 21d post-treatment. A 6h infusion of OA to untreated rats resulted in a reduction of the BUI for ARG and ORN to 51% and 62% of the control levels, respectively. Reductions of a similar magnitude were noted with both amino acids following the 15 sec OA bolus, indicating direct interaction of OA with the transport site in both cases. OA administered by either route abolished the enhancement of BUI for ORN, but did not further inhibit the BUI for ARG in the TAA-treated animals. The results indicate that some as yet unspecified factors released from damaged liver either modify the structure or conformation of the gamma + transporter at the BBB from the normally ARG-preferring to the ORN-preferring state, or activate (induce) a different transporter specific for ORN which is normally latent.
Albrecht
J
J
Department of Neuropathology, Polish Academy of Sciences, Warsaw, Poland.
Hilgier
W
W
Januszewski
S
S
Quack
G
G
D000818:Animals; D001120:Arginine / Q000378:metabolism*; D001812:Blood-Brain Barrier; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D056486:Chemical and Drug Induced Liver Injury / Q000150:complications / Q000378:metabolism*; D004151:Dipeptides / Q000494:pharmacology*; D006501:Hepatic Encephalopathy / Q000139:chemically induced / Q000378:metabolism; D007262:Infusions, Intravenous; D008239:Lysine / Q000378:metabolism*; D008297:Male; D009952:Ornithine / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013853:Thioacetamide / Q000633:toxicity*
D004151:Dipeptides; D013853:Thioacetamide; D001120:Arginine; D009952:Ornithine; C002939:ornithylaspartate; D008239:Lysine