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

Environ Mol Mutagen. Apr-May 2007;48(3-4):307-21. doi: 10.1002/em.20298.

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.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Anti-HIV Agents / blood
  • Anti-HIV Agents / pharmacokinetics*
  • Anti-HIV Agents / therapeutic use
  • Biomarkers / analysis
  • DNA / metabolism
  • DNA Damage*
  • Female
  • Fetal Blood / metabolism
  • HIV Infections / drug therapy
  • HIV Infections / prevention & control
  • Humans
  • Infant, Newborn
  • 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
  • Zidovudine / blood
  • Zidovudine / pharmacokinetics*
  • Zidovudine / therapeutic use

Substances

  • Anti-HIV Agents
  • Biomarkers
  • Reverse Transcriptase Inhibitors
  • Lamivudine
  • Zidovudine
  • DNA