Metabolism of the carbocyclic nucleoside analogue carbovir, an inhibitor of human immunodeficiency virus, in human lymphoid cells.

Important note: Information in this article was accurate in 1991. The state of the art may have changed since the publication date.

Metabolism of the carbocyclic nucleoside analogue carbovir, an inhibitor of human immunodeficiency virus, in human lymphoid cells.

Biochemistry. 1990 Oct 23;29(42):9839-43. Unique Identifier : AIDSLINE MED/91104892
Bondoc LL Jr; Shannon WM; Secrist JA 3d; Vince R; Fridland A; Department of Biochemical and Clinical Pharmacology, St. Jude; Children's Research Hospital, Memphis, Tennessee 38101.

Abstract: Carbovir (CBV) is a highly selective carbocyclic nucleoside inhibitor of HIV replication in human lymphocytes and is potentially useful in the treatment of AIDS [Vince et al. (1988) Biochem. Biophys. Res. Commun. 156, 1046-1053]. Using human lymphoid cells severely deficient in nucleoside kinases, we were able to identify the route of activation of CBV metabolism. The present studies have demonstrated that CBV is anabolized to the mono-, di-, and triphosphates and to guanosine 5'-triphosphate in CCRF-CEM cells. Conversion to GTP amounted to 15-20% of the total analogue nucleotides formed in the cells and may arise from CBV through depurination and salvage via HGPRT. Evidence was obtained that neither deoxycytidine kinase, adenosine kinase, or mitochondrial deoxyguanosine kinase is primarily involved in the initial step of phosphorylation of CBV in CCRF-CEM cells. In contrast, earlier studies [Johnson & Fridland (1989) Mol. Pharmacol. 36, 291-295] showed that a cytosolic 5'-nucleotidase catalyzes the activation of CBV to the monosphosphate. Other biochemical effects examined showed that the nucleobases hypoxanthine and adenine, but not guanine, their respective nucleosides, and the dideoxynucleosides 2',3'-dideoxyinosine, 2',3'-dideoxyguanosine, and 3'-azido-3'-deoxythymidine produced significant increased accumulation of CBV nucleotides in CEM cells. The exact mechanism for this potentiation of CBV phosphorylation has not been elucidated but may be due to a modulating effect of intracellular nucleotides on 5'-nucleotidase activity.

Keywords: Antiviral Agents/*METABOLISM Biotransformation Cells, Cultured Dideoxynucleosides/*METABOLISM Human Hypoxanthine Phosphoribosyltransferase/DEFICIENCY/METABOLISM HIV/*DRUG EFFECTS Nucleosides/METABOLISM/PHARMACOLOGY Phosphorylation Support, Non-U.S. Gov't Support, U.S. Gov't, P.H.S. T-Lymphocytes/*METABOLISM Virus Replication/DRUG EFFECTS 5'-Nucleotidase/METABOLISM JOURNAL ARTICLE
910530
M9150909

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