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Query: UNIPROT:P00492 (hypoxanthine-guanine phosphoribosyltransferase)
 2,385 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The metabolic fate of transported guanosine was examined in adult rat cardiac myocytes. Freshly isolated cells were incubated with 50 microM 8-[3H]-guanosine and the purine nucleoside phosphorylase (PNP) inhibitor acyclovir, and the nucleotide products extracted and examined for radiolabel distribution. Acyclovir inhibited guanosine incorporation into the 5'-nucleotide pool up to 66%. The drug did not inhibit guanosine transport. Other experiments using 5'-[3H]-guanosine and 8-[14C]-guanosine in concert as metabolic tracers showed both tritium and radiocarbon in the guanine nucleotide products. We concluded from this study that both a kinase (probably adenosine kinase) and the enzyme pair purine nucleoside phosphorylase/hypoxanthine-guanine phosphoribosyltransferase are responsible for guanosine salvage in heart cells.
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PMID:Guanosine metabolism in adult rat cardiac myocytes: inhibition by acyclovir and analysis of a metabolic pathway. 140 8

The herpes simplex virus (HSV) thymidine kinase (tk) gene was transfected into Chinese hamster ovary (CHO) 51-11 gly- cells to test its effect on the cytotoxic and mutagenic activity of anti-herpetic nucleoside analogues. Insertion of the viral tk was verified by Southern blot analysis, by sensitivity to acyclovir, and by elevated in vitro thymidine kinase (TK) activity. TK activity was increased by superinfection with a tk- virus and inhibited by antibody to viral TK. Acyclovir (ACV) was somewhat more cytotoxic in the 51-D3 cell line that expresses the viral TK than in the 51-11 parent line. Growth in ACV did not increase over background mutations at the hprt locus. FIAC (2'-fluoro-5-iodio-aracytosine) was slightly cytotoxic to the parent 51-11 line and the tk-containing clone 51-D3. FMAU (2'-fluoro-5-methyl-arauracil) had pronounced cytotoxicity in both cell lines: the 50% survival points were 1.0 microM for 51-11 cells and 0.2 microM for 51-D3. The clone 51-D3 was more sensitive than 51-11 to low concentrations of FIAU (2'-fluoro-5-iodo-arauracil), and when treated with FIAU 51-D3 had a mutation frequency to glycine independence 5 times greater than that of 51-11 cells. With both cell lines the mutation frequency at the hprt locus did not increase after growth in the presence of FIAC or FIAU. A 7-fold increase in mutation frequency at the hprt locus was detected after 51-D3 cells were grown with iododeoxyuridine. Trifluorothymidine was more toxic to 51-D3 than to 51-11 cells and increased the mutation frequency 2-fold. Cytosine-beta-D-arabinofuranoside showed no differential cytotoxicity on the two cell lines and did not increase the mutation frequency at the hprt locus.
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PMID:A mammalian cell line designed to test the mutagenic activity of anti-herpes nucleosides. 303 17

Acyclovir [9-(2-hydroxyethoxymethyl)guanine], a clinically useful anti-herpesvirus agent, was a weak inhibitor (Ki = 190 microM) of hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) from human erythrocytes. Nevertheless, this acyclic nucleoside analog was a more effective inhibitor than were its natural counterparts, guanosine (Ki = 1400 microM) and deoxyguanosine (Ki = 570 microM). The two oxidized metabolites of acyclovir, 9-carboxymethoxymethylguanine (Ki = 720 microM) and 8-hydroxy-9-(2-hydroxyethoxymethyl)guanine (Ki greater than 2000 microM), were less inhibitory than was the parent drug. None of the phosphorylated metabolites of acyclovir was as potent an inhibitor of HGPRTase as was GMP (Ki = 4 microM). However, the Ki value for acyclovir monophosphate was similar to that of dGMP (12 microM). The Ki values for acyclovir diphosphate (8.3 microM) and triphosphate (30 microM) were less than those for dGDP (110 microM) and dGTP (140 microM). The levels of these phosphate esters of acyclovir in cultured monkey kidney (Vero) and human embryo fibroblast (WI38) cells exposed to therapeutic levels of the drug were well below the observed Ki values. However, in herpesvirus-infected WI38 cells the levels of the phosphate esters of acyclovir were high enough potentially to inhibit the enzyme. Although inhibition of this enzyme by the phosphorylated metabolites of acyclovir may occur in these infected cells, concentrations of the drug very much higher than the EC50 concentration were required to achieve inhibitory levels. It is, therefore, unlikely that this inhibition contributes significantly to the antiviral activity.
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PMID:Effects of acyclovir and its metabolites on hypoxanthine-guanine phosphoribosyltransferase. 663 69