Plasma and cellular markers of 3′-azido-3′-dideoxythymidine (AZT) metabolism as indicators of DNA damage in cord blood mononuclear cells from infants receiving prepartum NRTIs
Several systemic and cellular markers of 3′‐azido‐3′‐dideoxythymidine (AZT) metabolism and AZT incorporation into nuclear DNA were measured in cord blood from uninfected infants born to HIV‐1‐infected mothers receiving prepartum therapies based on AZT or AZT in combination with 2′,3′‐dideoxy‐3′‐thia...
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| Veröffentlicht in: | Environmental and molecular mutagenesis 2007-04, Vol.48 (3-4), p.307-321 |
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| creator | Meng, Quanxin Olivero, Ofelia A. Fasco, Michael J. Bellisario, Ronald Kaminsky, Laurence Pass, Ken A. Wade, Nancy A. Abrams, Elaine J. Nesel, Carol J. Ness, Roberta B. Bigbee, William L. O'Neill, J. Patrick Walker, Dale M. Poirier, Miriam C. Walker, Vernon E. |
| description | Several systemic and cellular markers of 3′‐azido‐3′‐dideoxythymidine (AZT) metabolism and AZT incorporation into nuclear DNA were measured in cord blood from uninfected infants born to HIV‐1‐infected mothers receiving prepartum therapies based on AZT or AZT in combination with 2′,3′‐dideoxy‐3′‐thiacytidine (3TC). In addition, the relationships among these pharmacological end points, levels of AZT‐DNA incorporation, and the previously reported mutagenic responses in these infants were evaluated. AZT‐ and 3TC‐specific radioimmunoassays (RIAs), or HPLC coupled with AZT‐RIA, were used to measure plasma levels of AZT and the AZT‐glucuronide, and cellular levels of AZT, phosphorylated AZT, and DNA incorporation of AZT or 3TC in cord blood mononuclear cells from treated infants compared with unexposed controls born to HIV‐uninfected mothers. Fewer infants had detectable AZT‐DNA incorporation levels in the group exposed to AZT (71%; n = 7) compared with those receiving AZT‐3TC (100%; n = 21), and the mean AZT‐DNA incorporation for AZT‐exposed infants (14.6 ± 6.3 AZT/106 nucleotides) was significantly lower than that in AZT‐3TC exposed infants (51.6 ± 10.2 AZT/106 nucleotides; P = 0.028). Low levels of 3TC‐DNA incorporation found in a few AZT‐3TC‐exposed newborns correlated with AZT‐DNA incorporation values in the same samples. Among the metabolites studied, there were positive correlations between levels of AZT‐diphosphate and AZT‐triphosphate, and AZT‐triphosphate and AZT‐DNA incorporation, in nucleoside analog‐exposed infants. Levels of AZT‐DNA incorporation, however, did not correlate well with the reported frequencies of somatic mutations in the same population of nucleoside analog‐treated children. While these data support the continued use of AZT‐based therapies during pregnancy, infants receiving prepartum AZT should be monitored long‐term for adverse health effects. Environ. Mol. Mutagen., 2007. © 2007 Wiley‐Liss, Inc. |
| doi_str_mv | 10.1002/em.20298 |
| format | Article |
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Patrick ; Walker, Dale M. ; Poirier, Miriam C. ; Walker, Vernon E.</creator><creatorcontrib>Meng, Quanxin ; Olivero, Ofelia A. ; Fasco, Michael J. ; Bellisario, Ronald ; Kaminsky, Laurence ; Pass, Ken A. ; Wade, Nancy A. ; Abrams, Elaine J. ; Nesel, Carol J. ; Ness, Roberta B. ; Bigbee, William L. ; O'Neill, J. Patrick ; Walker, Dale M. ; Poirier, Miriam C. ; Walker, Vernon E. ; for the Study Team</creatorcontrib><description>Several systemic and cellular markers of 3′‐azido‐3′‐dideoxythymidine (AZT) metabolism and AZT incorporation into nuclear DNA were measured in cord blood from uninfected infants born to HIV‐1‐infected mothers receiving prepartum therapies based on AZT or AZT in combination with 2′,3′‐dideoxy‐3′‐thiacytidine (3TC). In addition, the relationships among these pharmacological end points, levels of AZT‐DNA incorporation, and the previously reported mutagenic responses in these infants were evaluated. AZT‐ and 3TC‐specific radioimmunoassays (RIAs), or HPLC coupled with AZT‐RIA, were used to measure plasma levels of AZT and the AZT‐glucuronide, and cellular levels of AZT, phosphorylated AZT, and DNA incorporation of AZT or 3TC in cord blood mononuclear cells from treated infants compared with unexposed controls born to HIV‐uninfected mothers. Fewer infants had detectable AZT‐DNA incorporation levels in the group exposed to AZT (71%; n = 7) compared with those receiving AZT‐3TC (100%; n = 21), and the mean AZT‐DNA incorporation for AZT‐exposed infants (14.6 ± 6.3 AZT/106 nucleotides) was significantly lower than that in AZT‐3TC exposed infants (51.6 ± 10.2 AZT/106 nucleotides; P = 0.028). Low levels of 3TC‐DNA incorporation found in a few AZT‐3TC‐exposed newborns correlated with AZT‐DNA incorporation values in the same samples. Among the metabolites studied, there were positive correlations between levels of AZT‐diphosphate and AZT‐triphosphate, and AZT‐triphosphate and AZT‐DNA incorporation, in nucleoside analog‐exposed infants. Levels of AZT‐DNA incorporation, however, did not correlate well with the reported frequencies of somatic mutations in the same population of nucleoside analog‐treated children. While these data support the continued use of AZT‐based therapies during pregnancy, infants receiving prepartum AZT should be monitored long‐term for adverse health effects. Environ. Mol. Mutagen., 2007. © 2007 Wiley‐Liss, Inc.</description><identifier>ISSN: 0893-6692</identifier><identifier>EISSN: 1098-2280</identifier><identifier>DOI: 10.1002/em.20298</identifier><identifier>PMID: 17358024</identifier><language>eng</language><publisher>Hoboken: Wiley Subscription Services, Inc., A Wiley Company</publisher><subject>3TC-DNA incorporation ; Anti-HIV Agents - blood ; Anti-HIV Agents - pharmacokinetics ; Anti-HIV Agents - therapeutic use ; AZT-DNA incorporation ; Biomarkers - analysis ; DNA - metabolism ; DNA Damage ; Female ; Fetal Blood - metabolism ; HIV Infections - drug therapy ; HIV Infections - prevention & control ; Human immunodeficiency virus ; Humans ; Infant, Newborn ; lamivudine ; Lamivudine - pharmacokinetics ; Leukocytes, Mononuclear - metabolism ; Maternal-Fetal Exchange ; Pregnancy ; Pregnancy Complications, Infectious - drug therapy ; Pregnancy Complications, Infectious - prevention & control ; Reverse Transcriptase Inhibitors - blood ; Reverse Transcriptase Inhibitors - pharmacokinetics ; Reverse Transcriptase Inhibitors - therapeutic use ; transplacental genotoxicity ; zidovudine ; Zidovudine - blood ; Zidovudine - pharmacokinetics ; Zidovudine - therapeutic use</subject><ispartof>Environmental and molecular mutagenesis, 2007-04, Vol.48 (3-4), p.307-321</ispartof><rights>Copyright © 2007 Wiley‐Liss, Inc.</rights><rights>(c) 2006 Wiley-Liss, Inc.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3888-d06879bc7ca5bacbe0dda41c374fbf20f4a698794da3ef19be10fc009184045a3</citedby><cites>FETCH-LOGICAL-c3888-d06879bc7ca5bacbe0dda41c374fbf20f4a698794da3ef19be10fc009184045a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fem.20298$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fem.20298$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27903,27904,45553,45554</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17358024$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Meng, Quanxin</creatorcontrib><creatorcontrib>Olivero, Ofelia A.</creatorcontrib><creatorcontrib>Fasco, Michael J.</creatorcontrib><creatorcontrib>Bellisario, Ronald</creatorcontrib><creatorcontrib>Kaminsky, Laurence</creatorcontrib><creatorcontrib>Pass, Ken A.</creatorcontrib><creatorcontrib>Wade, Nancy A.</creatorcontrib><creatorcontrib>Abrams, Elaine J.</creatorcontrib><creatorcontrib>Nesel, Carol J.</creatorcontrib><creatorcontrib>Ness, Roberta B.</creatorcontrib><creatorcontrib>Bigbee, William L.</creatorcontrib><creatorcontrib>O'Neill, J. Patrick</creatorcontrib><creatorcontrib>Walker, Dale M.</creatorcontrib><creatorcontrib>Poirier, Miriam C.</creatorcontrib><creatorcontrib>Walker, Vernon E.</creatorcontrib><creatorcontrib>for the Study Team</creatorcontrib><title>Plasma and cellular markers of 3′-azido-3′-dideoxythymidine (AZT) metabolism as indicators of DNA damage in cord blood mononuclear cells from infants receiving prepartum NRTIs</title><title>Environmental and molecular mutagenesis</title><addtitle>Environ. Mol. Mutagen</addtitle><description>Several systemic and cellular markers of 3′‐azido‐3′‐dideoxythymidine (AZT) metabolism and AZT incorporation into nuclear DNA were measured in cord blood from uninfected infants born to HIV‐1‐infected mothers receiving prepartum therapies based on AZT or AZT in combination with 2′,3′‐dideoxy‐3′‐thiacytidine (3TC). In addition, the relationships among these pharmacological end points, levels of AZT‐DNA incorporation, and the previously reported mutagenic responses in these infants were evaluated. AZT‐ and 3TC‐specific radioimmunoassays (RIAs), or HPLC coupled with AZT‐RIA, were used to measure plasma levels of AZT and the AZT‐glucuronide, and cellular levels of AZT, phosphorylated AZT, and DNA incorporation of AZT or 3TC in cord blood mononuclear cells from treated infants compared with unexposed controls born to HIV‐uninfected mothers. Fewer infants had detectable AZT‐DNA incorporation levels in the group exposed to AZT (71%; n = 7) compared with those receiving AZT‐3TC (100%; n = 21), and the mean AZT‐DNA incorporation for AZT‐exposed infants (14.6 ± 6.3 AZT/106 nucleotides) was significantly lower than that in AZT‐3TC exposed infants (51.6 ± 10.2 AZT/106 nucleotides; P = 0.028). Low levels of 3TC‐DNA incorporation found in a few AZT‐3TC‐exposed newborns correlated with AZT‐DNA incorporation values in the same samples. Among the metabolites studied, there were positive correlations between levels of AZT‐diphosphate and AZT‐triphosphate, and AZT‐triphosphate and AZT‐DNA incorporation, in nucleoside analog‐exposed infants. Levels of AZT‐DNA incorporation, however, did not correlate well with the reported frequencies of somatic mutations in the same population of nucleoside analog‐treated children. While these data support the continued use of AZT‐based therapies during pregnancy, infants receiving prepartum AZT should be monitored long‐term for adverse health effects. Environ. Mol. Mutagen., 2007. © 2007 Wiley‐Liss, Inc.</description><subject>3TC-DNA incorporation</subject><subject>Anti-HIV Agents - blood</subject><subject>Anti-HIV Agents - pharmacokinetics</subject><subject>Anti-HIV Agents - therapeutic use</subject><subject>AZT-DNA incorporation</subject><subject>Biomarkers - analysis</subject><subject>DNA - metabolism</subject><subject>DNA Damage</subject><subject>Female</subject><subject>Fetal Blood - metabolism</subject><subject>HIV Infections - drug therapy</subject><subject>HIV Infections - prevention & control</subject><subject>Human immunodeficiency virus</subject><subject>Humans</subject><subject>Infant, Newborn</subject><subject>lamivudine</subject><subject>Lamivudine - pharmacokinetics</subject><subject>Leukocytes, Mononuclear - metabolism</subject><subject>Maternal-Fetal Exchange</subject><subject>Pregnancy</subject><subject>Pregnancy Complications, Infectious - drug therapy</subject><subject>Pregnancy Complications, Infectious - prevention & control</subject><subject>Reverse Transcriptase Inhibitors - blood</subject><subject>Reverse Transcriptase Inhibitors - pharmacokinetics</subject><subject>Reverse Transcriptase Inhibitors - therapeutic use</subject><subject>transplacental genotoxicity</subject><subject>zidovudine</subject><subject>Zidovudine - blood</subject><subject>Zidovudine - pharmacokinetics</subject><subject>Zidovudine - therapeutic use</subject><issn>0893-6692</issn><issn>1098-2280</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp10c9uEzEQBvAVAtFQkHgC5BMqhy3j_e9jCKUtKgFVQUhcrFl7XAzrdbB3oeHEM8Eb8SRsmgAnTrbkn76x5kuShxyOOUD2lNxxBplobiUzDqJJs6yB28kMGpGnVSWyg-RejB8BOC9Edjc54HVeNpAVs-Tnmw6jQ4a9Zoq6buwwMIfhE4XIvGH5r-8_UvxmtU9vrtpq8teb4cPGWW17Ykfz96snzNGAre9sdAwjs722Cge_i3i-nDONDq9oemDKB83aznvNnO99P6qOppHb2ZGZ4N2EDPZDZIEU2S-2v2LrQGsMw-jY8nJ1Hu8ndwx2kR7sz8Pk7YuT1eIsvXh9er6YX6Qqb5om1VA1tWhVrbBsUbUEWmPBVV4XpjUZmAIrMYlCY06Gi5Y4GAUgeFNAUWJ-mDze5a6D_zxSHKSzcftR7MmPUWaQ16IGMcGjHVTBxxjIyHWw0xI3koPcFiTJyZuCJvponzm2jvQ_uG9kAukOfLUdbf4bJE9e_QncexsHuv7rpwZlVed1Kd8tT-Vi-ax8uYBLeZb_Bna4rRg</recordid><startdate>200704</startdate><enddate>200704</enddate><creator>Meng, Quanxin</creator><creator>Olivero, Ofelia A.</creator><creator>Fasco, Michael J.</creator><creator>Bellisario, Ronald</creator><creator>Kaminsky, Laurence</creator><creator>Pass, Ken A.</creator><creator>Wade, Nancy A.</creator><creator>Abrams, Elaine J.</creator><creator>Nesel, Carol J.</creator><creator>Ness, Roberta B.</creator><creator>Bigbee, William L.</creator><creator>O'Neill, J. 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Patrick</creatorcontrib><creatorcontrib>Walker, Dale M.</creatorcontrib><creatorcontrib>Poirier, Miriam C.</creatorcontrib><creatorcontrib>Walker, Vernon E.</creatorcontrib><creatorcontrib>for the Study Team</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Nucleic Acids Abstracts</collection><jtitle>Environmental and molecular mutagenesis</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Meng, Quanxin</au><au>Olivero, Ofelia A.</au><au>Fasco, Michael J.</au><au>Bellisario, Ronald</au><au>Kaminsky, Laurence</au><au>Pass, Ken A.</au><au>Wade, Nancy A.</au><au>Abrams, Elaine J.</au><au>Nesel, Carol J.</au><au>Ness, Roberta B.</au><au>Bigbee, William L.</au><au>O'Neill, J. Patrick</au><au>Walker, Dale M.</au><au>Poirier, Miriam C.</au><au>Walker, Vernon E.</au><aucorp>for the Study Team</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Plasma and cellular markers of 3′-azido-3′-dideoxythymidine (AZT) metabolism as indicators of DNA damage in cord blood mononuclear cells from infants receiving prepartum NRTIs</atitle><jtitle>Environmental and molecular mutagenesis</jtitle><addtitle>Environ. Mol. Mutagen</addtitle><date>2007-04</date><risdate>2007</risdate><volume>48</volume><issue>3-4</issue><spage>307</spage><epage>321</epage><pages>307-321</pages><issn>0893-6692</issn><eissn>1098-2280</eissn><abstract>Several systemic and cellular markers of 3′‐azido‐3′‐dideoxythymidine (AZT) metabolism and AZT incorporation into nuclear DNA were measured in cord blood from uninfected infants born to HIV‐1‐infected mothers receiving prepartum therapies based on AZT or AZT in combination with 2′,3′‐dideoxy‐3′‐thiacytidine (3TC). In addition, the relationships among these pharmacological end points, levels of AZT‐DNA incorporation, and the previously reported mutagenic responses in these infants were evaluated. AZT‐ and 3TC‐specific radioimmunoassays (RIAs), or HPLC coupled with AZT‐RIA, were used to measure plasma levels of AZT and the AZT‐glucuronide, and cellular levels of AZT, phosphorylated AZT, and DNA incorporation of AZT or 3TC in cord blood mononuclear cells from treated infants compared with unexposed controls born to HIV‐uninfected mothers. Fewer infants had detectable AZT‐DNA incorporation levels in the group exposed to AZT (71%; n = 7) compared with those receiving AZT‐3TC (100%; n = 21), and the mean AZT‐DNA incorporation for AZT‐exposed infants (14.6 ± 6.3 AZT/106 nucleotides) was significantly lower than that in AZT‐3TC exposed infants (51.6 ± 10.2 AZT/106 nucleotides; P = 0.028). Low levels of 3TC‐DNA incorporation found in a few AZT‐3TC‐exposed newborns correlated with AZT‐DNA incorporation values in the same samples. Among the metabolites studied, there were positive correlations between levels of AZT‐diphosphate and AZT‐triphosphate, and AZT‐triphosphate and AZT‐DNA incorporation, in nucleoside analog‐exposed infants. Levels of AZT‐DNA incorporation, however, did not correlate well with the reported frequencies of somatic mutations in the same population of nucleoside analog‐treated children. While these data support the continued use of AZT‐based therapies during pregnancy, infants receiving prepartum AZT should be monitored long‐term for adverse health effects. Environ. Mol. Mutagen., 2007. © 2007 Wiley‐Liss, Inc.</abstract><cop>Hoboken</cop><pub>Wiley Subscription Services, Inc., A Wiley Company</pub><pmid>17358024</pmid><doi>10.1002/em.20298</doi><tpages>15</tpages></addata></record> |
| fulltext | fulltext |
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| ispartof | Environmental and molecular mutagenesis, 2007-04, Vol.48 (3-4), p.307-321 |
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| source | MEDLINE; Wiley Online Library Journals Frontfile Complete |
| subjects | 3TC-DNA incorporation Anti-HIV Agents - blood Anti-HIV Agents - pharmacokinetics Anti-HIV Agents - therapeutic use AZT-DNA incorporation Biomarkers - analysis DNA - metabolism DNA Damage Female Fetal Blood - metabolism HIV Infections - drug therapy HIV Infections - prevention & control Human immunodeficiency virus Humans Infant, Newborn lamivudine Lamivudine - pharmacokinetics Leukocytes, Mononuclear - metabolism Maternal-Fetal Exchange Pregnancy Pregnancy Complications, Infectious - drug therapy Pregnancy Complications, Infectious - prevention & control Reverse Transcriptase Inhibitors - blood Reverse Transcriptase Inhibitors - pharmacokinetics Reverse Transcriptase Inhibitors - therapeutic use transplacental genotoxicity zidovudine Zidovudine - blood Zidovudine - pharmacokinetics Zidovudine - therapeutic use |
| title | Plasma and cellular markers of 3′-azido-3′-dideoxythymidine (AZT) metabolism as indicators of DNA damage in cord blood mononuclear cells from infants receiving prepartum NRTIs |
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