Tin-protoporphyrin potentiates arsenite-induced DNA strand breaks, chromatid breaks and kinetochore-negative micronuclei in human fibroblasts.
Numerous reports have shown that oxidative stress is involved in arsenite-induced genetic damage. Arsenite is also a potent inducer of heme oxygenase (HO)-1. To understand whether HO-1 could function as a cellular antioxidant and protect cells from arsenite injury, the effects of tin-protoporphyrin (SnPP), a competitive inhibitor of HO-1, on arsenite-induced genetic damage were examined in human skin fibroblasts (HFW). In the present study, we found that SnPP at 100 microM significantly potentiated arsenite-induced cytotoxicity, DNA strand breaks (assayed by alkaline single cell gel electrophoresis(SCGE)), and chromatid breaks. Although arsenite alone mainly induced kinetochore-plus micronuclei (K(+)-MN), SnPP only synergistically enhanced kinetochore-negative micronuclei (K(-)-MN). The increase in K(-)-MN by SnPP cotreatment was consistent with the increase in DNA strand breaks and chromatid breaks caused by SnPP. However, at higher arsenite doses, K(+)-MN was significantly reduced by SnPP. Pretreatment of HFW cells with hemin, an inducer of HO-1, significantly attenuated the cytotoxicity of arsenite. Therefore, the present results suggest that HO-1 induction by arsenite plays certain roles in protecting cells from arsenite-induced injury.
Ho
I C
IC
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
Yih
L H
LH
Kao
C Y
CY
Lee
T C
TC
D018053:Arsenites / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002869:Chromosome Aberrations; D020552:Comet Assay; D004247:DNA / Q000187:drug effects* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors; D006801:Humans; D007231:Infant, Newborn; D018386:Kinetochores; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology*; D048629:Micronuclei, Chromosome-Defective / Q000187:drug effects*; D011524:Protoporphyrins / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D018053:Arsenites; D004791:Enzyme Inhibitors; D008665:Metalloporphyrins; D011524:Protoporphyrins; D004247:DNA; C032628:tin protoporphyrin IX; D006419:Heme Oxygenase (Decyclizing); C015001:arsenite