Evidence for the induction of a new deoxycytidine kinase in cells infected with herpes virus

Perera, P A J; Morrison, J. M.

doi:10.1042/bj1170021pb

Cited by 12 publications

(5 citation statements)

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“…Both of these enzymes are coded for by the herpesvirus genome (Jamieson et aI., 1974;Mar and Huang, 1979;Perera and Morrison, 1970; Thouless and Skinner, 1971). Acyclovir is selectively phosphorylated by the herpescoded deoxynucleoside kinase to its monophosphate form (Elion et aI., 1977;Fyfe et aI., 1978).…”

mentioning

confidence: 98%

Clinical Pharmacokinetics of Acyclovir

Laskin

1983

Clinical Pharmacokinetics

127

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Acyclovir is a selective anti-herpes virus agent. At present it is available in topical and intravenous formulations; an oral formulation is currently being developed.Absorption of acyclovir after oral administration is slow, variable and incomplete. The bioavailability of oral acyclovir is low and decreases with increasing dosage. The average time to peak concentrations is approximately 2 hours and achievable peak concentrations following oral administration (600mg every 4 hours) are less than 6 pmol/L with current oral dosage forms.Acyclovir tissue and fluid concentrations can be determined accurately and sensitively by high-performance liquid chromatography, radioimmunoassay. and by virus inhibition (bioassay). Acyclovir demonstrates biexponential elimination. with a terminal plasma halflife of 2 to 3 hours in patients with normal renal function. The volume of the central compartment (21 L/I.73m!) and the apparent volume of distribution at steady-state (48 L/ 1. 73m!) are approximately that of extracellular fluid and total body water. respectively. The drug is distributed into all tissues. with concentrations in the kidney being the highest (10 times the simultaneous plasma concentration) and in central nervous tissue the lowest (25 to 70% of the corresponding plasma concentration). Acyclovir enters the cerebrospinal fluid. saliva and vaginal secretions at concentrations inhibitory to herpes simplex virus. The drug is poorly protein bound. in the range of 9 to 22%.Acyclovir is eliminated mainly via the kidney by glomerular filtration and renal tubular secretion. with only a small percentage of the dose being oxidised to 9-carboxymethoxymethylguanine (which is the only significant metabolite of acyclovir in man). Acyclovir has dose-independent kinetics. The renal clearance of acyclovir is about 75 to 80% o/the total body clearance and approximately 3jold greater than creatinine clearance. Probenecid reduces acyclovir renal clearance by 32%. presumably by inhibiting tubular secretion of the drug.In anuric patients. acyclovir is slowly eliminated with a terminal plasma half-life of approximately 20 hours. The acyclovir total body clearance (29 ml/min/I.73m2) is only 10% of that seen in patients without renal impairment. Acyclovir is readily haemodialysable with an extraction coefficient of 0.45 and a dialysis clearance of 82 ml/min using a hollow fibre single-pass dialyser. A single haemodialysis (6h) reduces acyclovir concentrations by 60%.The pharmacokinetics of acyclovir in children (greater than 1 year of age) are similar to those in adults. In neonates. the total body clearance is about one-third 0/ that found in children and adults. The terminal plasma half-life is slightly longer in the neonate. The toxicity of acyclovir appears to be minimal and consists of local irritation after extravasation. phlebitis. and occasionally reversible elevations in serum creatinine. espe-

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confidence: 98%

Clinical Pharmacokinetics of Acyclovir

Laskin

1983

Clinical Pharmacokinetics

127

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“…After infection with HSV, however, the levels of activity of several enzymes involved in nucleic acid metabolism have been shown to increase. These enzymes include thymidine kinase (12), DNA polymerase (6,8,9,13), DNase (9), dTMP kinase (18), dCMP deaminase (8), and deoxycytidine kinase (6,19).…”

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confidence: 99%

DNA synthesis and DNA polymerase activity of herpes simplex virus type 1 temperature-sensitive mutants

Aron¹,

Purifoy²,

Schaffer³

1975

J Virol

120

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Fifteen temperature-sensitive mutants of herpes simplex virus type 1 were studied with regard to the relationship between their ability to synthesize viral DNA and to induce viral DNA polymerase (DP) activity at permissive (34 C) and nonpermissive (39 C) temperatures. At 34 C, all mutants synthesized viral DNA, while at 39 C four mutants demonstrated a DNA' phenotype, three were DNA', and eight were DNA-. DNA' mutants induced levels of DP activity similar to those of the wild-type virus at both temperatures, and DNA' mutants induced reduced levels of DP activity at 39 C but not at 34 C. Among the DNAmutants, three were DP', two were DP', and three showed reduced DP activity at 34 C with no DP activity at 39 C. DNA-, DPmutants induced the synthesis of a temperature-sensitive DP as determined by in vivo studies.

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“…Immunological evidence indicates that the induced polymerase is antigenically different from the control cell enzyme (Keir etal., 1966b). This provides fairly strong evidence that the induced enzyme is distinct from that of the host cell, and the indications are that this is also the case for the other enzymes mentioned above (Klemperer etal., 1967;Morrison & Keir, 1968;Buchan & Watson, 1969;Buchan et al, 1970a,b;Perera, 1970).…”

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confidence: 99%

Deoxycytidylate deaminase. Evidence for a new enzyme in cells infected by the virus of herpes simplex

Rolton

Keir

1974

Biochemical Journal

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The activities of dCMP deaminase and DNA polymerase I increased twofold and fivefold in BHK-21/C13 cells after infection by the virus of herpes simplex. The increases were greatly diminished, and under certain conditions prevented, by inclusion of actinomycin D or cycloheximide in the cell-virus system during the infective cycle. The dCMP deaminase purified from infected cells harvested 8h after infection differed from the deaminase purified from non-infected cells inasmuch as (a) it was more resistant to heating at 37 degrees C; (b) the substrate (dCMP) concentration at half-maximum velocity was lower; (c) maximum activation was achieved by a lower concentration of dCTP; (d) it was more resistant to inhibition by dTTP; and (e) it behaved differently when assayed in the presence of a herpes-virus-specific antiserum. The DNA polymerase activity in the infected cells was markedly decreased in the presence of the herpes-virus-specific antiserum.

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Evidence for the induction of a new deoxycytidine kinase in cells infected with herpes virus

Cited by 12 publications

References 1 publication

Clinical Pharmacokinetics of Acyclovir

Clinical Pharmacokinetics of Acyclovir

DNA synthesis and DNA polymerase activity of herpes simplex virus type 1 temperature-sensitive mutants

Deoxycytidylate deaminase. Evidence for a new enzyme in cells infected by the virus of herpes simplex

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