Oxidative stress promotes the development of transformation: involvement of a potent mutagenic lipid peroxidation product, acrolein.
The effect of intracellular oxidative stress on the development of cell transformation was studied. Mouse embryo C3H/10T1/2 fibroblasts pre-treated with benzo[a] pyrene, developed transformed foci on exposure to free radical generators, such as 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH) and 3-morpholinosydnonimine hydrochloride (SIN-1). These compounds generate peroxyl radicals and peroxynitrite, respectively. Neither AAPH nor SIN-1 alone induced transformation. The level of intracellular antioxidants, such as alpha-tocopherol and glutathione (GSH), decreased with time of exposure to the free radical generators, whereas the addition of exogenous alpha-tocopherol, GSH and ebselen showed a reduction in the frequency of transformation. An early event during exposure to AAPH and SIN-1 was the generation of acrolein, a highly mutagenic lipid peroxidation product, which was suppressed by the addition of alpha-tocopherol. Furthermore, it was confirmed that acrolein induced the transformation of cells which were pre-treated with benzo[a]pyrene but not of the untreated cells. These results suggest that acrolein may act as an important mediator of cell transformation under oxidative stress.
Takabe
W
W
Research Center for Advanced Science and Technology, The University of Tokyo, Komaba, Meguro, Tokyo 153-8904, Japan.
Niki
E
E
Uchida
K
K
Yamada
S
S
Satoh
K
K
Noguchi
N
N
D000171:Acrolein / Q000493:pharmacokinetics* / Q000633:toxicity*; D000578:Amidines / Q000493:pharmacokinetics / Q000633:toxicity; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001564:Benzo(a)pyrene / Q000633:toxicity; D001711:Biotransformation; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005609:Free Radicals / Q000493:pharmacokinetics / Q000633:toxicity; D015227:Lipid Peroxidation; D051379:Mice; D008809:Mice, Inbred C3H; D008981:Molsidomine / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000633:toxicity; D009153:Mutagens / Q000493:pharmacokinetics / Q000633:toxicity*; D009566:Nitrates / Q000378:metabolism / Q000633:toxicity; D020030:Nitric Oxide Donors / Q000493:pharmacokinetics / Q000633:toxicity; D016877:Oxidants / Q000493:pharmacokinetics / Q000633:toxicity; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D014810:Vitamin E / Q000494:pharmacology
D000578:Amidines; D000975:Antioxidants; D005609:Free Radicals; D009153:Mutagens; D009566:Nitrates; D020030:Nitric Oxide Donors; D016877:Oxidants; D017382:Reactive Oxygen Species; D014810:Vitamin E; C039642:peroxynitric acid; D001564:Benzo(a)pyrene; C002385:linsidomine; C046728:2,2'-azobis(2-amidinopropane); D000171:Acrolein; D008981:Molsidomine