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.

Mouse erythrocytes as carriers for coencapsulated alcohol and aldehyde dehydrogenase obtained by electroporation in vivo survival rate in circulation, organ distribution and ethanol degradation.

Alcohol dehydrogenase and aldehyde dehydrogenase (ADH and ALDH) have been coencapsulated into mouse erythrocytes by an electroporation technique. The optimal conditions were achieved as follows: 420 V, four pulses of 1 ms every 15 min. at 37 degrees C, completed by resealing: 1 h at 37 degrees C. An encapsulation yield ranging from 11-12% was obtained for ADH+ALDH-loaded erythrocytes. Carrier cell recovery was 52%. Electroporated-RBCs observed under Scanning electron microscopy exhibited a tendency toward invaginated sphero-stomatocytes. These invaginations were not found in electroporated/resealed RBCs. The intravenous administration of 51Cr-RBCs manifested a bimodal pharmacokinetic profile: an initial phase (t1/2alpha) with a rapid decrease of plasma 51Cr-RBCs followed by a slow and prolonged elimination phase (t1/2beta). The values corresponding to in vivo survival rate during the elimination phase indicated that the survival rate of 51Cr-electroporated loaded-RBCs was slightly lower (t1/2beta, 4.5 days) than 51Cr-native RBCs (t1/2beta, 5.3 days). The mean clearance values from blood of electroporated 51Cr-RBCs (unloaded and loaded) were higher (0.51 %51Cr/day and 0.54 %51Cr/day, respectively) than the obtained for native 51Cr-RBCs (0.18 %51Cr/day). The target organs for electroporated RBCs proved to be the same as for native RBCs. However, electroporated RBCs showed highest accumulation in liver, spleen and lung, since they were promptly recognized by the reticuloendothelium system. Mice induced to the state of acute ethanol intoxication and treated with ADH+ALDH-RBCs clearly showed a lower level of ethanol concentration in plasma (less than 43% ethanol) than the intoxicated mice treated with native RBCs. En consequence the clearance values of ethanol from blood in intoxicated mice treated with ADH+ALDH-RBCs (0.39 ml/min) were higher than the treated with native RBCs (0.20 ml/min). The results obtained suggest that ADH+ALDH-loaded erythrocytes could be used as a potential carrier system for in vivo removal of high levels of ethanol from blood caused by excessive alcohol consumption.