Differential inhibition of DNA synthesis in human T cells by the cigarette tar components hydroquinone and catechol.
Hydroquinone (HQ), catechol, and phenol exist in microgram quantities in cigarette tar and represent the predominant form of human exposure to benzene. Exposure of human T lymphoblasts (HTL) in vitro to 50 microM HQ or 50 microM catechol decreased IL-2-dependent DNA synthesis and cell proliferation by >90% with no effect on cell viability. Phenol had no effect on HTL proliferation at concentrations up to 1 mm. The addition of HQ or catechol to proliferating HTL blocked 3H-TdR uptake by >90% within 2 hr without significantly affecting 3H-UR uptake, suggesting that both compounds inhibit a rate-limiting step in DNA synthesis. However, the effects of HQ and catechol appear to involve different mechanisms. Ferric chloride (FeCl3) reversed the inhibitory effect of catechol, but not HQ, corresponding with the known ability of catechol to chelate iron. HQ, but not catechol, caused a decrease in transferrin receptor (TfR, CD71) expression, comparable to the level observed in IL-2-starved cells. HQ also inhibited DNA synthesis in cultures of transformed Jurkat T lymphocytes, primary and transformed fibroblasts, and mink lung epithelial cells, indicating that its antiproliferative effect was not restricted to IL-2 mediated proliferation. However, DNA synthesis by primary lymphocytes was more sensitive to HQ (IC50 = 6 microM) than that of the transformed Jurkat T cell line (IC50 = 37 microM) or primary human fibroblasts (IC50 = 45 microM), suggesting that normal lymphocytes may be particularly sensitive to HQ. The effects of HQ and catechol on DNA synthesis could be partially reversed by a combination of adenosine deoxyribose and guanosine deoxyribose, suggesting that both compounds may inhibit ribonucleotide reductase.
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Transplantation Immunology and Histocompatibility Laboratory, Albany Medical College, Albany, New York, 12208, USA.
Aubrey
M T
MT
Christian
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Freed
B M
BM
D000818:Animals; D002396:Catechols / Q000037:antagonists & inhibitors / Q000633:toxicity*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis*; D003864:Depression, Chemical; D006801:Humans; D006873:Hydroquinones / Q000037:antagonists & inhibitors / Q000633:toxicity*; D007376:Interleukin-2 / Q000096:biosynthesis; D007501:Iron / Q000494:pharmacology; D051379:Mice; D012313:RNA / Q000096:biosynthesis; D011990:Receptors, Transferrin / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D014028:Tobacco Smoke Pollution / Q000009:adverse effects / Q000032:analysis*
D002396:Catechols; D006873:Hydroquinones; D007376:Interleukin-2; D011990:Receptors, Transferrin; D014028:Tobacco Smoke Pollution; D012313:RNA; D004247:DNA; D007501:Iron; C031927:hydroquinone