Linked Life Data

12019082

Source:http://linkedlifedata.com/resource/pubmed/id/12019082

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
6
pubmed:dateCreated
2002-5-20
pubmed:abstractText
beta-L-Thymidine (L-dT) and beta-L-2'-deoxycytidine (L-dC) are potent and highly specific inhibitors of hepatitis B virus (HBV) replication both in vivo and in vitro (50% effective concentrations, 0.19 to 0.24 microM in 2.2.15 cells). The intracellular metabolisms of L-dT and L-dC were investigated in HepG2 cells and primary cultured human hepatocytes. L-dT and L-dC were extensively phosphorylated in both cell types, with the 5'-triphosphate derivative being the predominant metabolite. In HepG2 cells, the 5'-triphosphate levels were 27.7 +/- 12.1 and 72.4 +/- 1.8 pmol/10(6) cells for L-dT and L-dC, respectively. In primary human hepatocytes, the 5'-triphosphate levels were 16.5 +/- 9.8 and 90.1 +/- 36.4 pmol/10(6) cells for L-dT and L-dC, respectively. Furthermore, a choline derivative of L-dCDP was detected at concentrations of 15.8 +/- 1.8 and 25.6 +/- 0.1 pmol/10(6) cells in human hepatocytes and HepG2 cells, respectively. In HepG2 cells exposed to L-dC, the 5'-monophosphate and 5'-triphosphate derivatives of beta-L-2'-deoxyuridine (L-dUMP and L-dUTP, respectively) were also observed, reaching intracellular concentrations of 6.7 +/- 0.4 and 18.2 +/- 1.0 pmol/10(6) cells, respectively. In human hepatocytes, L-dUMP and L-dUTP were detected at concentrations of 5.7 +/- 2.4 and 43.5 +/- 26.8 pmol/10(6) cells, respectively. It is likely that deamination of L-dCMP by deoxycytidylate deaminase leads to the formation of L-dUMP, as the parent compound, L-dC, was not a substrate for deoxycytidine deaminase. The intracellular half-lives of L-dTTP, L-dCTP, and L-dUTP were at least 15 h, with intracellular concentrations of each metabolite remaining above their respective 50% inhibitory concentrations for the woodchuck hepatitis virus DNA polymerase for as long as 24 h after removal of the drug from cell cultures. Exposure of HepG2 cells to L-dT in combination with L-dC led to concentrations of the activated metabolites similar to those achieved with either agent alone. These results suggest that the potent anti-HBV activities of L-dT and L-dC are associated with their extensive phosphorylation.
pubmed:commentsCorrections
http://linkedlifedata.com/resource/pubmed/commentcorrection/12019082-11120971, http://linkedlifedata.com/resource/pubmed/commentcorrection/12019082-1321132, http://linkedlifedata.com/resource/pubmed/commentcorrection/12019082-1336341, http://linkedlifedata.com/resource/pubmed/commentcorrection/12019082-2139281, http://linkedlifedata.com/resource/pubmed/commentcorrection/12019082-2430286, http://linkedlifedata.com/resource/pubmed/commentcorrection/12019082-2834034, http://linkedlifedata.com/resource/pubmed/commentcorrection/12019082-7628294, http://linkedlifedata.com/resource/pubmed/commentcorrection/12019082-8092819, http://linkedlifedata.com/resource/pubmed/commentcorrection/12019082-8328741, http://linkedlifedata.com/resource/pubmed/commentcorrection/12019082-8385948, http://linkedlifedata.com/resource/pubmed/commentcorrection/12019082-8781347, http://linkedlifedata.com/resource/pubmed/commentcorrection/12019082-8960066, http://linkedlifedata.com/resource/pubmed/commentcorrection/12019082-9011789, http://linkedlifedata.com/resource/pubmed/commentcorrection/12019082-9705540
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
0066-4804
pubmed:author
pubmed:issnType
Print
pubmed:volume
46
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1728-33
pubmed:dateRevised
2009-11-18
pubmed:meshHeading
pubmed:year
2002
pubmed:articleTitle
Pharmacology of beta-L-thymidine and beta-L-2'-deoxycytidine in HepG2 cells and primary human hepatocytes: relevance to chemotherapeutic efficacy against hepatitis B virus.
pubmed:affiliation
Department of Pharmacology, University of Alabama at Birmingham, USA.
pubmed:publicationType
Journal Article