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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
Author(s) -
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 Ver E.
Publication year - 2007
Publication title -
environmental and molecular mutagenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1
H-Index - 87
eISSN - 1098-2280
pISSN - 0893-6692
DOI - 10.1002/em.20298
Subject(s) - peripheral blood mononuclear cell , cord blood , immunology , dna , biology , virology , microbiology and biotechnology , genetics , in vitro
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/10 6 nucleotides) was significantly lower than that in AZT‐3TC exposed infants (51.6 ± 10.2 AZT/10 6 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.