Protective Effects of Facilitated Removal of Blood Alcohol and Acetaldehyde Against Liver Injury in Animal Models Fed Alcohol and Anti-HIV Drugs.

BACKGROUND: We previously developed enzyme nanoparticles (ENP) of alcohol metabolism. This study was to evaluate protective effects of facilitated removal of blood alcohol and/or acetaldehyde on anti-HIV drugs and alcohol-induced liver injuries. METHODS: ENP were prepared for degrading alcohol completely (ENP1) or partially into acetaldehyde (ENP2), which were applied to mice of acute binge or chronic-binge alcohol feeding in the presence of antivirals (ritonavir and lopinavir). Liver pathologies were examined to assess the protective effects of ENP. RESULTS: In the acute model, ENP1 and ENP2 reduced the blood alcohol concentration (BAC) by 41 and 32%, respectively, within 4 hr, whereas in control without ENP, BAC was reduced only by 15%. Blood acetaldehyde concentration (BADC) was increased by 39% in alcohol-fed mice treated with ENP2 comparing to control. No significant effects of the anti-HIV drugs on BAC or BADC were observed. Plasma alanine aminotransferase (ALT) and expression of liver TNF-α were both significantly increased in the alcohol-fed mice, which were normalized by ENP1. In the presence of the antivirals, ALT was partially reduced by ENP1 or ENP2. In the chronic model, inflammation, fatty liver, and ALT were increased, which were deteriorated by the antivirals. ENP1 partially reduced BAC, BADC, ALT, and expression of inflammation markers of TNF-α, F4/80, and IL-6 and lipogenic factors of ACC, LXRα, and SREBP1. ENP2 reduced BAC without significant effects on ALT, inflammation, or lipogenesis. Antivirals and alcohol synergistically increased expression of organelle stress markers of CHOP, sXBP-1, ATF6, and GCP60. ENP1 reduced BAC, CHOP, and sXbp-1. However, no effects of ENP1 were found on ATF6 or GCP60. CONCLUSIONS: Removal of blood alcohol and acetaldehyde by the ENP protects the liver against alcoholic injuries, and the protection is less effective in chronic alcohol and antiviral feeding due to additional drug-induced organelle stresses.

Temporal response of hepatic threonine dehydrogenase in chickens to the initial consumption of a threonine-imbalanced diet.

Amino acid imbalances contribute to higher requirements of amino acids than would occur if the dietary profile of amino acids perfectly matched the requirements. The mechanisms of imbalances have not been fully elucidated. Because threonine dehydrogenase (TDH) activity in liver mitochondria increases in chicks and rats subjected to threonine imbalance, the current study was carried out to determine whether the change in TDH activity occurs rapidly enough after the consumption of an imbalanced diet to be considered a possible primary metabolic response. In a series of experiments, Leghorn chicks were allowed free access to a semipurified basal diet marginally limited in threonine or the same diet containing a mixture of indispensable amino acids (IAA) lacking threonine to cause a threonine imbalance. In the first experiment, dietary supplements of 5.5 and 11.1% IAA were used to determine a level of supplement that would cause a robust response in the specific activity of TDH. Feed intake, body weight gains and efficiency of feed utilization were lower and specific activities of TDH were higher in chicks fed 11.1% IAA than in those fed 5.5% IAA. In subsequent experiments, hepatic TDH activities and plasma amino acid profiles of the control and experimental groups were determined at 1. 5, 3, 6, 12 and 24 h after the first offering of the diet containing 11.1% IAA. The specific activities of TDH in chicks fed the IAA supplement were 40-150% higher (P < 0.05) and plasma threonine concentrations were 42-53% lower (P < 0.05) than in chicks fed the basal diet at all times except 1.5 h. These results indicate that changes in the capacity for threonine degradation via TDH may occur in the liver within a few hours after the consumption of a threonine-imbalanced diet and suggest the possibility that altered TDH activity may contribute to the increased threonine requirement associated with threonine imbalance.

Striatal extracellular choline and acetylcholine in choline-free plasma rats.

Choline (Ch)-free plasma rats were induced successfully by intravenous (IV) injection of choline oxidase (ChO) (16). However, brain acetylcholine (ACh) levels were not affected by ChO treatment, maintaining the same levels as those in controls, although brain Ch levels were significantly decreased. To clarify the reasons for this, in vivo microdialysis was carried out in the treated rats' striata. The ChO treatment induced not only a 70% decrease of extracellular Ch levels but also a 40% decrease of extracellular ACh levels, reflecting the amount of ACh released from cholinergic terminals. In addition, plasma-bound Ch levels and choline acetyltransferase (CAT) and acetylcholinesterase (AChE) activities in the brain were examined in the rats receiving ChO treatment. No significant differences from controls were observed in these levels. The results suggest that: approximately 70% of striatal extracellular Ch is physiologically supplied from circulating plasma-free Ch; the inhibition of ACh release is related to the maintenance of tissue (intraneuronal) ACh levels under the condition of halting of the supply of free Ch from blood to the brain; if there is a compensative supply of free Ch from de novo synthesis, autocannibalism, or plasma-bound Ch, this may be supplied within neuronal cells, because the level of extracellular-free Ch maintained its depressed level even 11-14 h after ChO treatment.

Effects of choline-free plasma induced by choline oxidase on regional levels of choline and acetylcholine in rat brain.

Choline-free plasma (CFP) was induced in rats by intravenous (IV) injection of 56.0 x 10(2) units kg-1 of choline oxidase (ChO) which completely metabolized the free Ch circulating in the plasma for at least 15.0 h and caused subsequent significant decrease in the concentration of free Ch in the three brain regions examined, the striatum, hippocampus, and cortex. However, the treatment did not affect concentrations of acetylcholine (ACh) in these regions. By contrast, intraperitoneal (IP) injection of 1.0 mmol kg-1 Ch chloride resulted in a maximum concentration of free Ch in plasma in 5 min, after which tissue Ch in all regions examined increased (p < 0.001). Concomitant increases were observed in cortical and hippocampal ACh (p < 0.05) 20 min after the injection. It is thus suggested that the brain may possess compensative mechanisms to prevent the supply of free Ch from circulating to the brain during synthesis of ACh in the brain. It is also suggested that the CFP rat would be a useful and readily available animal model for future study.