Intracellular metabolism of 2',3'-dideoxynucleosides in duck hepatocyte primary cultures.

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Kitos TE, Tyrrell DL

Intracellular metabolism of 2',3'-dideoxynucleosides in duck hepatocyte primary cultures.

Biochem Pharmacol. 1995 May 11;49(9):1291-302.

PubMed ID

7763311 [ View in PubMed

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Abstract

The intracellular fate of the potent duck hepatitis B virus (DHBV) inhibitor 2,6-diaminopurine 2',3'-dideoxyriboside (ddDAPR), its deamination product 2',3'-dideoxyguanosine (ddG), and the less effective DHBV-inhibitor 2',3'-dideoxycytidine (ddC) was investigated in duck hepatocyte primary cultures. After a 1-min exposure of [3H]ddDAPR to duck blood, 95% of the compound was converted to ddG. Similarly, [3H]ddDAPR was converted rapidly to ddG in duck hepatocyte primary cultures, with ddG exhibiting resistance to further catabolism. The major pathway of ddG utilization in these cells was phosphorylation, yielding a concentration of 2.1 and 1.9 microM total ddG nucleotides after 5 and 26 hr, respectively, of exposure to 4 microM ddG. Removal of exogenous ddG led to a rapid (T1/2 = 1.6 hr) decrease in the total intracellular ddG nucleotide pools. Duck hepatocytes treated with 4 microM ddC exhibited a time-dependent accumulation of ddC nucleotides, culminating in a maximum intracellular total ddC nucleotide concentration of 1.4 microM after 24-26 hr. The intracellular total ddC nucleotide level decreased with a T1/2 of 4.4 hr following the removal of exogenous ddC. The formation of ddC nucleotides was reduced in the presence of excess 2'-dideoxycytidine implicating deoxycytidine kinase in the initial step of ddC phosphorylation. A 25-fold excess of 2'-deoxycytidine had no effect on ddG phosphorylation in duck hepatocytes. However, a 92% inhibition of ddG nucleotide formation occurred in duck hepatocytes treated for 5 hr with 4 microM [3H]dG + 100 microM adenosine in the presence of the adenosine deaminase inhibitor 2'-deoxycoformycin, suggesting that, in these cells, adenosine kinase is involved in the ddG phosphorylation process.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Zalcitabine	Deoxycytidine kinase	Protein	Humans	Unknown	Substrate	Details