Young S. Jung

Impaired Sulfur-Amino Acid Metabolism and Oxidative Stress in Nonalcoholic Fatty Liver Are Alleviated by Betaine Supplementation in Rats

Nonalcoholic fatty liver is involved in the development of nonalcoholic steatohepatitis and chronic liver injury. Impairment of hepatic transsulfuration reactions is suggested to be critically linked with alcoholic liver injury, but its role in nonalcoholic fatty liver remains unknown. We examined the early changes in sulfur-amino acid metabolism and their implication in nonalcoholic fatty liver disease (NAFLD). Male rats were provided with a standard liquid diet or a high-fat liquid diet (HF) for 3 wk. An additional group of rats received the HF diet supplemented with betaine (1%). HF diet intake elevated hepatic triglyceride and serum tumor necrosis factor-alpha (TNFalpha) concentrations. Antioxidant capacity of liver cytosol against hydroxyl and peroxyl radicals was reduced significantly. Hepatic S-adenosylmethionine (SAM) and glutathione (GSH) decreased, but hypotaurine and taurine concentrations increased. Methionine adenosyltransferase (MAT) activity, not its concentration, was depressed, whereas both activity and concentration of cysteine dioxygenase and GSH S-transferase were elevated. Betaine supplementation of the HF diet inhibited hepatic fat accumulation and serum TNFalpha elevation. The decrease in cytosolic antioxidant capacity was also prevented. MAT activity and its concentration were induced significantly. Hepatic SAM and GSH increased and elevation of hypotaurine and taurine was depressed. The results indicate that the metabolism of S-containing substances is significantly disturbed by the HF diet, suggesting a causal role of impairment of hepatic transsulfuration reactions in NAFLD. Betaine supplementation protects the liver from nonalcoholic steatosis and oxidative stress most probably via its effects on the transsulfuration reactions.

Alleviation of acute ethanol-induced liver injury and impaired metabolomics of S-containing substances by betaine supplementation

Oxidative stress is suggested to play a key role in the development of alcoholic liver injury. We investigated the induction of oxidative damage in association with changes in hepatic concentrations of sulfur-containing substances in mice challenged with binge-like ethanol administration. Also the protective effect of dietary betaine against ethanol-induced liver injury was determined. Serum alanine aminotransferase activity, TNFalpha level, and hepatic malondialdehyde level were increased significantly by ethanol administration. Hepatic Cyp2e1 was induced to 250% of control. Ethanol administration decreased hepatic S-adenosylmethionine, cysteine, and glutathione, but elevated hypotaurine and taurine levels. Betaine supplied in drinking water for 2 weeks attenuated the induction of alcoholic liver injury and Cyp2e1 significantly. Reduction of hepatic S-adenosylmethionine and glutathione was alleviated, and elevation of hypotaurine and taurine was depressed. The results suggest that betaine may protect the liver against ethanol-induced oxidative injury most probably via its effects on the sulfur-amino acid metabolism.

Alleviation of dimethylnitrosamine-induced liver injury and fibrosis by betaine supplementation in rats.

Previous studies suggested that betaine intake might antagonize the induction of oxidative stress-mediated acute liver injury through regulation of the sulfur-amino acid metabolism. In this study we examined the protective effects of betaine on chronic liver injury and fibrosis induced by dimethylnitrosamine (DMN). Male rats were supplemented with betaine (1%, w/v) in drinking water from 2 weeks prior to the initiation of DMN treatment (10mg/(kg day), i.p., 3 days/week, for 1, 2, or 4 weeks) until sacrifice. Induction of liver injury was determined by quantifying serum alanine aminotransferase, aspartate aminotransferase activities, bilirubin levels, hepatic xenobiotic-metabolizing capacity, histopathological changes and 4-hydroxyproline levels. Development of oxidative injury was estimated by malondialdehyde (MDA) levels and total oxyradical scavenging capacity (TOSC) of liver and serum toward hydroxyl, peroxyl radicals, and peroxynitrite. Progressive changes in the parameters of liver injury and fibrosis were evident in the rats challenged with DMN. Elevation of MDA levels in liver was significant before the onset of a change in any parameters determined in this study. Betaine supplementation markedly attenuated the induction of hepatotoxicity and fibrosis by DMN. Elevation of MDA and the reduction of TOSC were also depressed significantly. Development of liver injury corresponded well with the induction of oxidative stress in rats treated with DMN, both of which are inhibited effectively by betaine supplementation. It is suggested that betaine may protect liver from fibrogenesis by maintaining the cellular antioxidant capacity.

Ethanol-induced liver injury and changes in sulfur amino acid metabolomics in glutathione peroxidase and catalase double knockout mice.

BACKGROUND/AIMS Oxidative stress via generation of reactive oxygen species is suggested to be the major mechanism of alcohol-induced liver injury. We investigated the effects of glutathione peroxidase-1 and catalase double deficiency (Gpx-1(-/-)/Cat(-/-)) on liver injury and changes in the sulfur amino acid metabolism induced by binge ethanol administration. METHODS Ethanol (5 g/kg) was administered orally to the wild-type and the Gpx-1(-/-)/Cat(-/-) mice every 12 h for a total of three doses. Mice were sacrificed 6 h after the final dose. RESULTS The Gpx-1/Cat deficiency alone increased malondialdehyde levels in liver significantly. Hepatic methionine adenosyltransferase (MAT) activity and S-adenosylmethionine levels were decreased, however, glutathione contents were not changed. Ethanol administration to the Gpx-1(-/-)/Cat(-/-) mice increased the elevation of serum alanine aminotransferase activity, plasma homocysteine levels, hepatic fat accumulation and lipid peroxidation compared with the wild-type animals challenged with ethanol. Also the reduction of MAT activity and S-adenosylmethionine levels was enhanced, but MATI/III expression was increased significantly. CONCLUSIONS The results indicate that Gpx-1 and Cat have critical roles in the protection of liver against binge ethanol exposure. Augmentation of ethanol-induced oxidative stress may be responsible for the impairment of the transsulfuration reactions and the aggravation of acute liver injury in the Gpx-1(-/-)/Cat(-/-) mice.

Induction of hepatic CYP2E1 by a subtoxic dose of acetaminophen in rats: increase in dichloromethane metabolism and carboxyhemoglobin elevation.

Dichloromethane (DCM) is metabolically converted to carbon monoxide mostly by CYP2E1 in liver, resulting in elevation of blood carboxyhemoglobin (COHb) levels. We investigated the effects of a subtoxic dose of acetaminophen (APAP) on the metabolic elimination of DCM and COHb elevation in adult female rats. APAP, at 500 mg/kg i.p., was not hepatotoxic as measured by a lack of change in serum aspartate aminotransferase, alanine aminotransferase, and sorbitol dehydrogenase activities. In rats pretreated with APAP at this dose, the COHb elevation resulting from administration of DCM (3 mmol/kg i.p.) was enhanced significantly. Also blood DCM levels were reduced, and its disappearance from blood appeared to be increased. Hepatic CYP2E1-mediated activities measured with chlorzoxazone, p-nitrophenol, and p-nitroanisole as substrates were all induced markedly in microsomes of rats treated with APAP. Aminopyrine N-demethylase activity was also increased slightly, but significantly. Western blot analysis showed that APAP treatment induced the expression of CYP2E1 and CYP3A proteins. Neither hepatic glutathione contents nor glutathione S-transferase activity was changed by the dose of APAP used. The results indicate that, contrary to the well known hepatotoxic effects of this drug at large doses, a subtoxic dose of APAP may induce CYP2E1, and to a lesser degree, CYP3A expression. This is the first report that APAP can increase cytochrome P450 (P450)-mediated hepatic metabolism and the resulting toxicity of a xenobiotic in the whole animal. The pharmacological/toxicological significance of induction of P450s by a subtoxic dose of APAP is discussed.

Partner Assignment Algorithm for Cooperative Diversity in Mobile Communication Systems

Most work on cooperative diversity has assumed that the cooperating group (source and partners) and the associated average channel conditions between terminals (source, partners, and destination) are predetermined. In practical situations, however, it is important to develop the efficient algorithms for assigning the terminals with good inter-user channels for cooperating groups. In this paper, we propose the partner assignment algorithm for cooperative diversity in mobile communication systems. The proposed partner assignment algorithm is investigated by using the path loss model for mobile communication systems. Numerical results show that the proposed partner assignment algorithm provides the comparable probability of cooperative transmission to the partner assignment algorithm using exhaustive search. The probability of cooperative transmission increases with the number of users, which gives potential benefits of practical implementation to user cooperation in mobile communication systems. The proposed partner assignment algorithm also provides the tradeoff between probability of cooperative transmission, cooperative diversity gain, and the amount of average SNR information of inter-user channels

Amplify-and-Forward Cooperative Transmission with Multiple Relays Using Phase Feedback

Cooperative transmission obtains the spatial diversity gains created by sharing antennas of terminals in wireless networks. Although the amplify-and-forward (AF) cooperative transmission has the advantages of low implementation complexity and simplicity compared to the decode-and- forward (DF) cooperative transmission, studies on the AF cooperative transmission with multiple relays have not been sufficiently investigated. In this paper, we introduce the AF cooperative transmission with multiple relays using phase feedback. Simulation results show that the proposed schemes obtain the diversity gain according to the number of the cooperating terminals. The performance of proposed scheme using tolerable quantized feedback is close to that of proposed scheme using full feedback.

Pharmacokinetics of oltipraz in diabetic rats with liver cirrhosis

Background and purpose:  The incidence of diabetes mellitus is increased in patients with liver cirrhosis. Oltipraz is currently in trials to treat patients with liver fibrosis and cirrhosis induced by chronic hepatitis types B and C and is primarily metabolized via hepatic cytochrome P450 isozymes CYP1A1/2, 2B1/2, 2C11, 2D1 and 3A1/2 in rats. We have studied the influence of diabetes mellitus on pharmacokinetics of oltipraz and on expression of hepatic, CYP1A, 2B1/2, 2C11, 2D and 3A in rats with experimental liver cirrhosis.

Pharmacokinetic Parameters of Chlorzoxazone and Its Main Metabolite, 6-Hydroxychlorzoxazone, after Intravenous and Oral Administration of Chlorzoxazone to Liver Cirrhotic Rats with Diabetes Mellitus

Protein expression of the hepatic CYP2E1 has been reported to be increased in diabetic rats. This enzyme is the primary metabolizer of chlorzoxazone (CZX) to 6-hydroxychlorzoxazone (OH-CZX). Although patients with liver cirrhosis have a higher prevalence of diabetes mellitus, there have been no reported studies on the protein expression of CYP2E1 in rats induced to have liver cirrhosis and diabetes mellitus by injection of N-dimethylnitrosamine followed by streptozotocin [liver cirrhosis with diabetes mellitus (LCD) rats]. Thus, in the present study, the pharmacokinetics of CZX and OH-CZX were evaluated in LCD rats. Compared with control rats, LCD rats had significantly decreased (by 62%) total liver protein and significantly increased (by 124%) protein expression of CYP2E1, but the intrinsic clearance (Clint; formation of OH-CZX per milligram protein) was comparable in both groups of rats. As a result, the relative Clint was also comparable for the two groups. Thus, OH-CZX formation in LCD and control rats was expected to be similar. As expected, after i.v. (20 mg/kg) and p.o. (50 mg/kg) administration of CZX, the area under the curve (AUC) of OH-CZX was comparable in control and LCD rats (i.v., 571 ± 85.8 and 578 ± 413 μg · min/ml, respectively; p.o., 1540 ± 338 and 2170 ± 1070 μg · min/ml, respectively). In LCD rats, the AUCOH-CZX/AUCCZX ratio was similar to the value in control rats after i.v. and p.o. administration. These results indicate that OH-CZX can be used as a chemical probe to assess the activity of CYP2E1 in LCD rats.

New measure of coding gain for space-time trellis codes

The existing measures of coding gain for the space-time trellis code do not adequately evaluate coding gain for frame error rate. In this paper, a new measure of coding gain is proposed. The space-time trellis code having the largest proposed measure of coding gain is obtained through computer search.