Ah. Hammond et Jr. Fry, EFFECTS OF CULTURE DURATION, CYTOCHROME-P-450 INHIBITION AND GLUTATHIONE DEPLETION ON TOXICITY OF DIVERSE XENOBIOTICS, Toxicology in vitro, 10(3), 1996, pp. 315-321
The toxicity of six compounds was investigated in rat hepatocyte cultu
res: 3-hr cultures were exposed to toxin between 3 and 24 hr after pla
ting and 24-hr cultures between 24 and 48 hr after plating. The toxici
ties of sodium dodecyl sulfate (SDS), allyl alcohol and 8-methoxypsora
len (8-MOP) were similar in 3- and 24-hr cultures, whereas precocene I
I, 1,3-dichloro-2-propanol (DC2P) and coumarin were all less toxic in
24-hr cultures than in 3-hr cultures. Pretreatment of cultures with th
e cytochrome P-450 inhibitor 1-aminobenzotriazole abolished the toxici
ties of coumarin and DC2P and decreased the toxicity of precocene II i
n both 3- and 24-hr cultures. In addition, the toxicity of precocene I
I appeared to correlate with the activity of the high-affinity form of
7-methoxycoumarin O-demethylase. Pretreatment of cultures with diethy
l maleate (DEM) or buthionine sulfoximine (BSO) increased the toxicity
of allyl alcohol, precocene II and DC2P, but not SDS. DEM enhanced th
e toxicity of 8-MOP in 3-hr cultures and BSO enhanced the toxicity of
coumarin in 24-hr cultures. It was also demonstrated that the onset of
DC2P toxicity was observed earlier in BSO-treated cultures than in DE
M-treated cultures. For the compounds tested, culture age seems less i
mportant in determining toxicity than choice of glutathione-depleting
agent. Copyright (C) 1996 Elsevier Science Ltd.