Transplacental drug transfer and frequency of Tk and Hprt lymphocyte mutants and peripheral blood micronuclei in mice treated transplacentally with zidovudine and lamivudine.
In previous studies, we have shown that zidovudine (3'-azido-3'-deoxythymidine; AZT), but not lamivudine [(-)2',3'-dideoxy-3'-thiacytidine; 3TC], is genotoxic when administered to neonatal mice, and that 3TC when coadministered with AZT does not alter the responses observed with AZT alone (Von Tungeln et al. [2002] Carcinogenesis 23:1427-1432). We now have investigated the transplacental transfer of these drugs and the induction of mutants and micronuclei in the neonatal offspring. From gestational day 12 until parturition, female C57BL/6N and C57BL/6N/Tk(+/-) mice, which had been mated to male C3H/HeNMTV mice, were treated daily by gavage with AZT, 3TC, or a combination of AZT and 3TC. In both dams and fetuses, AZT was found at much higher levels than its metabolites, AZT 5'-glucuronide and 3'-azido-3'-deoxythymidine. In the neonates, AZT and the mixture of AZT and 3TC caused a decrease in the percentage of reticulocytes (RETs) and an increase in the percentage of micronucleated RETs and micronucleated normochromatic erythrocytes. When assessed 3 weeks after birth, AZT and the combination of AZT and 3TC increased the thymidine kinase (Tk) mutant frequency in male mice; at 5 weeks, 3TC increased the Tk mutant frequency in female mice. The increase in Tk mutants in mice treated with AZT and the mixture of AZT and 3TC was associated with loss of the wild-type (Tk(+)) allele (loss of heterozygosity; LOH) and a pattern of discontinuous LOH. These data indicate that AZT, 3TC, and the combination of AZT and 3TC are transplacental mutagens and that the increase in mutants resulting from AZT is due mainly to large-scale genetic alterations.
Von Tungeln
Linda S
LS
Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, Arkansas, USA.
Williams
Lee D
LD
Doerge
Daniel R
DR
Shaddock
Joseph G
JG
McGarrity
Lynda J
LJ
Morris
Suzanne M
SM
Mittelstaedt
Roberta A
RA
Heflich
Robert H
RH
Beland
Frederick A
FA
D000818:Animals; D000831:Animals, Newborn; D019380:Anti-HIV Agents / Q000493:pharmacokinetics / Q000633:toxicity*; D005260:Female; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D019259:Lamivudine / Q000493:pharmacokinetics / Q000633:toxicity*; D019656:Loss of Heterozygosity / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects; D008297:Male; D008431:Maternal-Fetal Exchange; D051379:Mice; D008815:Mice, Inbred Strains; D048629:Micronuclei, Chromosome-Defective / Q000139:chemically induced; D009153:Mutagens / Q000493:pharmacokinetics / Q000633:toxicity*; D020641:Polymorphism, Single Nucleotide / Q000187:drug effects; D011247:Pregnancy; D018894:Reverse Transcriptase Inhibitors / Q000493:pharmacokinetics / Q000633:toxicity*; D013937:Thymidine Kinase / Q000235:genetics; D015215:Zidovudine / Q000493:pharmacokinetics / Q000633:toxicity*
D019380:Anti-HIV Agents; D009153:Mutagens; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D015215:Zidovudine; D007041:Hypoxanthine Phosphoribosyltransferase; D013937:Thymidine Kinase