title: Methylated bismuth, but not bismuth citrate or bismuth glutathione, induces cyto- and genotoxic effects in human cells in vitro.
abstract: Bismuth compounds are widely used in industrial processes and products. In medicine, bismuth salts have been applied in combination with antibiotics for the treatment of Helicobacter pylori infections, for the prevention of diarrhea, and in radioimmunotherapy. In the environment, bismuth ions can be biotransformed to the volatile bismuth compound trimethylbismuth (Me3Bi) by methanobacteria. Preliminary in-house studies have indicated that bismuth ions are methylated in the human colon by intestinal microflora following ingestion of bismuth-containing salts. Information concerning cyto- and genotoxicity of these biomethylated products is limited. In the present study, we investigated the cellular uptake of an organic bismuth compound [monomethylbismuth(III), MeBi(III)] and two other bismuth compounds [bismuth citrate (Bi-Cit) and bismuth glutathione (Bi-GS)] in human hepatocytes, lymphocytes, and erythrocytes using ICP-MS. We also analyzed the cyto- and genotoxic effects of these compounds to investigate their toxic potential. Our results show that the methylbismuth compound was better taken up by the cells than Bi-Cit and Bi-GS. All intracellularly detected bismuth compounds were located in the cytosol of the cells. MeBi(III) was best taken up by erythrocytes (36%), followed by lymphocytes (17%) and hepatocytes (0.04%). Erythrocytes and hepatocytes were more susceptible to MeBi(III) exposure than lymphocytes. Cytotoxic effects of MeBi(III) were detectable in erythrocytes at concentrations >4 microM, in hepatocytes at >130 microM, and in lymphocytes at >430 microM after 24 h of exposure. Cytotoxic effects for Bi-Cit and Bi-GS were much lower or not detectable in the used cell lines up to a tested concentration of 500 microM. Exposure of lymphocytes to MeBi(III) (250 microM for 1 h and 25 microM/50 microM for 24 h) resulted in significantly increased frequencies of chromosomal aberrations (CA) and sister chromatid exchanges (SCE), whereas Bi-Cit and Bi-GS induced neither CA nor SCE. Our study also showed an intracellular production of free radicals caused by MeBi(III) in hepatocytes but not in lymphocytes. These data suggest that biomethylation of bismuth ions by the intestinal microflora of the human colon leads to an increase in the toxicity of the primary bismuth salt.
authors.affiliation: Institute of Hygiene and Occupational Health, University Hospital, Hufelandstrasse 55, 45122 Essen, Germany.
authors.forename: U
authors.initials: U
authors.lastname: von Recklinghausen
authors.forename: L M
authors.initials: LM
authors.lastname: Hartmann
authors.forename: S
authors.initials: S
authors.lastname: Rabieh
authors.forename: J
authors.initials: J
authors.lastname: Hippler
authors.forename: A V
authors.initials: AV
authors.lastname: Hirner
authors.forename: A W
authors.initials: AW
authors.lastname: Rettenmeier
authors.forename: E
authors.initials: E
authors.lastname: Dopp
mesh_terms: D001729:Bismuth / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002849:Chromatography, Gas; D002869:Chromosome Aberrations / Q000139:chemically induced; D002951:Citrates / Q000737:chemistry; D003603:Cytotoxins / Q000633:toxicity*; D004249:DNA Damage / Q000187:drug effects*; D004912:Erythrocytes / Q000378:metabolism; D005978:Glutathione / Q000737:chemistry; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism; D008745:Methylation; D015394:Molecular Structure; D009153:Mutagens / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012854:Sister Chromatid Exchange / Q000187:drug effects / Q000235:genetics
chemical_list: D002951:Citrates; D003603:Cytotoxins; D009153:Mutagens; D017382:Reactive Oxygen Species; D005978:Glutathione; D001729:Bismuth