Jk. Kidney et Em. Faustman, MODULATION OF NITROSOUREA TOXICITY IN RODENT EMBRYONIC-CELLS BY O-6-BENZYLGUANINE, A DEPLETOR OF O-6-METHYLGUANINE-DNA METHYLTRANSFERASE, Toxicology and applied pharmacology, 133(1), 1995, pp. 1-11
Micromass culture systems of mesencephalon (CNS) and limb bud (LB) reg
ions were used to evaluate the impact of the O-6-methylguanine-DNA met
hyltransferase (MGMT) inhibitor, O-6-benzylguanine (BG), on ethylnitro
sourea (ENU) and methylnitrosourea (MNU)-induced in vitro toxicity. Th
ese primary rat embryo cells were preincubated with BG (2.5 mu M for C
NS; 10 mu M for LB) for 24 hr and then ENU (0-1708 mu M) or MNU (0-160
0 mu M) was added, Five days after culture initiation, cell survival w
as assessed using neutral red uptake and cell differentiation was asse
ssed using selective staining (Alcian blue in LB cultures and hematoxy
lin in CNS) and image analysis, In both LB and CNS cultures, preexposu
re to BG resulted in a significant increase in inhibition of different
iation following MNU exposure but no increase in cytotoxicity, There w
ere no statistically significant changes in the toxicity induced by EN
U in these differentiating cells consequent to BG preexposure. Our obs
ervations lend support to the idea of a specific role for DNA adducts
in defining MNU's toxic effects on cell viability and differentiation.
(C) 1995 Academic Press, Inc.