Metabolism of the anti-hepatitis C virus nucleoside beta-D-N4-hydroxycytidine in different liver cells.
نویسندگان
چکیده
Beta-D-N4-hydroxycytidine (NHC) was found to have selective anti-hepatitis C virus (HCV) activity in the HCV replicon system (clone A). The intracellular metabolism of tritiated NHC was investigated in the HCV replicon system, Huh-7 cells, HepG2 cells, and primary human hepatocytes. Incubation of cells with 10 microM radiolabeled NHC demonstrated extensive and rapid phosphorylation in all liver cells. Besides the 5'-mono, -di-, and -triphosphate metabolites of NHC, other metabolites were characterized. These included cytidine and uridine mono-, di-, and triphosphates. UTP was the predominant early metabolite in Huh-7 cells and primary human hepatocytes, suggesting deamination of NHC as the primary catabolic pathway. The intracellular half-lives of radiolabeled NHC-triphosphate and of CTP and UTP derived from NHC incubation in Huh-7 cells were calculated to be 3.0 +/- 1.3, 10.4 +/- 3.3, and 13.2 +/- 3.5 h (means +/- standard deviations), respectively. Studies using monkey and human whole blood demonstrated more-rapid deamination and oxidation in monkey cells than in human cells, suggesting that NHC may not persist long enough in plasma to be delivered to liver cells.
منابع مشابه
Metabolism of the Anti-Hepatitis C Virus Nucleoside -D-N-Hydroxycytidine in Different Liver Cells
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عنوان ژورنال:
- Antimicrobial agents and chemotherapy
دوره 48 12 شماره
صفحات -
تاریخ انتشار 2004