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

Abstract

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 periph eral lymphocytes has been investigated. 2 The stable epoxides 1,1,1 trichloropropene-2,3-oxide (100μM) and trans stilbene oxide (100μM) as well as metabolites generated from aflatoxin B1 (30μM) and naph thalene (100μM) by an extracellular metabolising system were toxic to isolated resting mononuclear leucocytes (MNLs), whereas glycidol (100μM), benzo[a]pyrene (100μM) and tamoxifen (50μM) were not. 3 The stable epoxides 1,1,1 trichloropropene-2,3-oxide (100μM) and trans stilbene oxide (100μM) but not glycidol (100μM) were toxic to dividing lymphocytes only after a 72-h exposure. Tamoxifen (30μM), aflatoxin B 1 (30μM) and their metabolites were also toxic to dividing lymphocytes. Benzo[a]pyrene (100μM) and naphthalene (100/μM) were not toxic either in the absence or presence of the extracel lular metabolising system. 4 Benzo[a]pyrene (100/μM) and aflatoxin B1 (30μM) 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.