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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

Department of Pharmacology and Therapeutics, University of Liverpool, PO Box 147, Liverpool, L69 3BX

MD Tingle

Department of Pharmacology and Therapeutics, University of Liverpool, PO Box 147, Liverpool, L69 3BX

MD Kelly

Department of Cell Biology, Toxicol Laboratories Limited, Bromyard Road Ledbury, Herefordshire, HR8 1LH, UK

BK Park

Department of Pharmacology and Therapeutics, University of Liverpool, PO Box 147, Liverpool, L69 3BX

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.

Key Words: epoxides • benzo[a]pyrene • aflatoxin B1 • naph thalene • tamoxifen • liver • lymphocytes

Human & Experimental Toxicology, Vol. 14, No. 6, 507-515 (1995)
DOI: 10.1177/096032719501400608


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