Evaluation of the generation of genotoxic and cytotoxic metabolites of benzo[a]pyrene, aflatoxin B1, naphthalene and tamoxifen using human liver microsomes and human lymphocytes.
1. The ability of model stable epoxides and metabolites generated by human liver microsomes from benzo[a]pyrene, aflatoxin B1, naphthalene and tamoxifen to produce cytotoxicity and genotoxicity in human peripheral lymphocytes has been investigated. 2. The stable epoxides 1,1,1 trichloropropene-2,3-oxide (100 microM) and trans stilbene oxide (100 microM) as well as metabolites generated from aflatoxin B1 (30 microM) and naphthalene (100 microM) by an extracellular metabolising system were toxic to isolated resting mononuclear leucocytes (MNLs), whereas glycidol (100 microM), benzo[a]pyrene (100 microM) and tamoxifen (50 microM) were not. 3. The stable epoxides 1,1,1 trichloropropene-2,3-oxide (100 microM) and trans stilbene oxide (100 microM) but not glycidol (100 microM) were toxic to dividing lymphocytes only after a 72-h exposure. Tamoxifen (30 microM), aflatoxin B1 (30 microM) and their metabolites were also toxic to dividing lymphocytes. Benzo[a]pyrene (100 microM) and naphthalene (100 microM) were not toxic either in the absence or presence of the extracellular metabolising system. 4. Benzo[a]pyrene (100 microM) and aflatoxin B1 (30 microM) were directly genotoxic to lymphocytes, this genotoxicity was significantly enhanced by the presence of the extracellular metabolising system. This indicates that both intracellular and extracellular bioactivation of these two compounds can produce genotoxicity. In contrast, naphthalene and tamoxifen were non-genotoxic.
Wilson
A S
AS
Department of Pharmacology and Therapeutics, University of Liverpool, UK.
Tingle
M D
MD
Kelly
M D
MD
Park
B K
BK
D000433:1-Propanol / Q000378:metabolism / Q000633:toxicity; D000328:Adult; D016604:Aflatoxin B1 / Q000378:metabolism / Q000633:toxicity; D001564:Benzo(a)pyrene / Q000378:metabolism / Q000633:toxicity; D002273:Carcinogens / Q000378:metabolism / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D004785:Environmental Pollutants / Q000378:metabolism / Q000633:toxicity*; D004852:Epoxy Compounds / Q000378:metabolism / Q000633:toxicity*; D004965:Estrogen Antagonists / Q000378:metabolism / Q000633:toxicity; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects*; D009153:Mutagens / Q000378:metabolism / Q000633:toxicity*; D009249:NADP / Q000378:metabolism; D009281:Naphthalenes / Q000378:metabolism / Q000633:toxicity; D020005:Propanols; D012854:Sister Chromatid Exchange / Q000187:drug effects / Q000235:genetics; D013091:Spermatogenesis / Q000187:drug effects; D013267:Stilbenes / Q000378:metabolism / Q000633:toxicity; D013601:T-Lymphocytes / Q000187:drug effects*; D013629:Tamoxifen / Q000378:metabolism / Q000633:toxicity; D014239:Trichloroepoxypropane / Q000378:metabolism / Q000633:toxicity
D002273:Carcinogens; D004785:Environmental Pollutants; D004852:Epoxy Compounds; D004965:Estrogen Antagonists; D009153:Mutagens; D009281:Naphthalenes; D020005:Propanols; D013267:Stilbenes; D013629:Tamoxifen; C031721:naphthalene; D014239:Trichloroepoxypropane; D001564:Benzo(a)pyrene; D009249:NADP; D000433:1-Propanol; D016604:Aflatoxin B1; C025906:stilbene oxide; C004312:glycidol