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Clearance of bacterial lipopolysaccharides and lipid A by the liver and the role of arginino-succinate synthase

Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Teikyo University, Kanagawa, Japan, moto-sth{at}pharm.teikyo-u.ac.jp

Shingo Ando

Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Teikyo University, Kanagawa, Japan

Takehiro Shinoda

Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Teikyo University, Kanagawa, Japan

Masatoshi Yamazaki

Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Teikyo University, Kanagawa, Japan

The liver is thought to be involved in the systemic clearance and detoxification of lipopolysaccharide (LPS). Argininosuccinate synthase (AS), a liver cytosolic urea cycle enzyme, has been found to bind to and inactivate LPS and lipid A. To elucidate the participation of AS in the clearance of LPS by liver and hepatocytes, we investigated the correlation between AS content and the removal of lipid A and LPS in vivo and in vitro, tracing levels of biological activity. A hepatotoxic model in which mice were injected with CCl₄ revealed a significant reduction in lipid A clearance along with liver failure on day 1; total body clearance was changed to 0.534 ml/min from 1.42 ml/min. AS content in liver concomitantly decreased to about half and AS leaked to blood at about 6 µg/ml. Total body clearance of i.v. injected AS was estimated at 0.083 ml/min, which predicted about 24-h leakage of AS after CCl₄ injection. The treatment also reduced the clearance of R-type LPSs to a lesser degree the larger its polysaccharide portion. S-type LPS, which has a large O-antigen polysaccharide, exhibited enhancement of clearance on CCl₄ treatment. When pretreated in vitro with AS and injected into normal mice, lipid A and R-type LPS showed a similar pattern of clearance of residual activities to the untreated forms, but S-type LPS exhibited enhancement of clearance. Comparison between different strains of mice revealed a correlation of AS content in liver and lipid A clearance, where the higher AS strain C3H/He mice showed a more rapid clearance than the lower AS strains C57BL/6 and BALB/c. Primary spheroid cultures of hepatocytes treated with 0.1 µM dexamethasone and 1 µM glucagon showed about a 2-fold increase in AS amount and a more rapid clearance of LPS from culture medium than untreated cells. These results suggest that AS in hepatocytes may be involved in the process of lipid A and LPS clearance and the extracellular leakage of AS may also participate in the systemic detoxification.

Key Words: Argininosuccinate synthase • clearance • endotoxin • lipid A • liver

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