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'-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.
Meng
Quanxin
Q
Wadsworth Center, New York State Department of Health, Albany, New York, USA.
Olivero
Ofelia A
OA
Fasco
Michael J
MJ
Bellisario
Ronald
R
Kaminsky
Laurence
L
Pass
Ken A
KA
Wade
Nancy A
NA
Abrams
Elaine J
EJ
Nesel
Carol J
CJ
Ness
Roberta B
RB
Bigbee
William L
WL
O'Neill
J Patrick
JP
Walker
Dale M
DM
Poirier
Miriam C
MC
Walker
Vernon E
VE
D019380:Anti-HIV Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D015415:Biomarkers / Q000032:analysis; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D005260:Female; D005312:Fetal Blood / Q000378:metabolism; D015658:HIV Infections / Q000188:drug therapy / Q000517:prevention & control; D006801:Humans; D007231:Infant, Newborn; D019259:Lamivudine / Q000493:pharmacokinetics; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008431:Maternal-Fetal Exchange; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000188:drug therapy / Q000517:prevention & control; D018894:Reverse Transcriptase Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D015215:Zidovudine / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use
D019380:Anti-HIV Agents; D015415:Biomarkers; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D015215:Zidovudine; D004247:DNA