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KMID : 0379519870030020129
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한국독성학회지
1987 Volume.3 No. 2 p.129 ~ p.141
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PROTECTIVE ACTION OF N-ACETYLCYSTEINE AGAINST HEPATOTOXIC AGENTS IN ISOLATED RAT LIVER CELLS
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Park Soo-Hee
Dong Mi-Sook
Kang Dong-Chul
Lee Ki-Wan
Cha Young-Nam
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Abstract
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Hepatocytes isolated from rats which have been pretreated with phenobarbital (80 mg/kg for 3 days), were able to take up N-acetylcysteine from surrounding medium and were able to synthesize the reduced glutathione (GSH^{ast}-3) intracellularly. The N-acetylcysteine is quickly deacetylated after the uptake and increases the pool size of cysteine, which was very low initially (5 nmol/10^6 cells). From this increased intracellular cysteine pool, GSH was synthesized. Freshly isolated rat hepatocytes contained a high level of GSH (30 nmol/10^6 cells), but upon incubation with the diethylmaleate, it was markedly decreased (10 nmol/10^6 cells). The hepatocytes with depleted GSH have lost viability upon incubations with acetaminophen (5mM) and paraquat (2 mM). However, when the N-acetylcysteine (1 mM) was added to this incubation condition, these chemical induced hepatocellular necrosis were prevented for longer durations. This N-acetylcysteine dependent protective effect against the hepatotoxic chemicals was lost by adding methionine sulfoximine (10 mM), an inhibitor of GSH biosynthesis. Both the carbontetrachloride (5 mM) and chioroform (5 mM) added to the incubation medium caused rapid losses of GSH and cell viability, even without the prior depletion of cellular GSH. However, again, if the 1mM N-acetylcysteine was supplemented, the rates of losses of GSH and cell viability were retarded in both cases. Even though large amounts of the added N-acetylcysteine was present in the cell, N-acetylcysteine conjugate of acetaminophen was not formed. Instead, only large amounts of GSH conjugate of the drug was produced. Thus, it is concluded that the added N-acetylcysteine is taken up and utilized for resynthesis of GSH. In turn, this resynthesized GSH contributes to the protection against cytotoxicity inducible with hepatotoxic drugs.
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KEYWORD
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N-acetylcysteine, Isolated rat hepatocytes, GSH biosynthesis, Hepatotoxic agents
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