MODULATION BY GLUTATHIONE OF DNA STRAND BREAKS INDUCED BY 4-(METHYLNITROSAMINO)-1-(3-PYRIDYL)-1-BUTANONE AND ITS ALDEHYDE METABOLITES IN RAT HEPATOCYTES

被引:16
作者
DEMKOWICZDOBRZANSKI, K [1 ]
CASTONGUAY, A [1 ]
机构
[1] UNIV LAVAL,SCH PHARM,CANC ETIOL & CHEMOPREVENT LAB,QUEBEC CITY G1K 7P4,QUEBEC,CANADA
关键词
D O I
10.1093/carcin/13.8.1447
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Activation of the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) produced methylating species and two aldehydes: formaldehyde and 4-oxo-4-(3-pyridyl)butanal (OPB). We investigated the modulation by glutathione of single-strand breaks (SSB) generated by N-methyl-N-nitrosourea (MNU) and the two aldehydes. Hepatocytes were simultaneously exposed to 0.2 mM MNU and to 0-2.00 mM formaldehyde or OPB for 4 h. Both aldehydes induced SSB in a dose-dependent manner. Formaldehyde and OPB exerted a synergistic effect on the formation of DNA SSB by MNU. It is postulated that both aldehydes interfere with DNA repair processes and thus increase the genotoxic effect of DNA methylating species. We investigated whether glutathione (GSH) could protect DNA from NNK-derived intermediates. Formaldehyde (2 mM) and OPB (2 mM) decreased intracellular GSH contents to 60 and 86% of control respectively. DL-Buthionine-[S,R]-sulfoximine (BSO) treatment reduced the GSH contents of hepatocytes to 19% of control but did not reduce the content of cytochrome P450 nor the metabolism of NNK. The frequency of DNA SSB induced by NNK, formaldehyde or OPB was significantly higher in GSH-depleted hepatocytes. GSH repletion with GSH monoethyl ester returned NNK-induced SSB to its initial frequency. OPB but not NNK nor formaldehyde induced double-strand breaks. We conclude that OPB and formaldehyde inhibit the repair of DNA damage induced by methylating species and that GSH reduces the level of DNA damage induced by NNK-derived reactive metabolites.
引用
收藏
页码:1447 / 1454
页数:8
相关论文
共 48 条
[1]   SYNTHESIS OF 5'-CARBOXY-N'-NITROSONORNICOTINE AND 5'-([C-14]CARBOXY)-N'-NITROSONORNICOTINE [J].
ABBASPOUR, A ;
HECHT, SS ;
HOFFMANN, D .
JOURNAL OF ORGANIC CHEMISTRY, 1987, 52 (15) :3474-3477
[2]   FAILURE OF GLUTATHIONE TO PREVENT LIVER-CANCER DEVELOPMENT IN RATS INITIATED WITH DIETHYLNITROSAMINE IN THE RESISTANT HEPATOCYTE MODEL [J].
AHLUWALIA, MB ;
ROTSTEIN, J ;
TATEMATSU, M ;
ROOMI, MW ;
FARBER, E .
CARCINOGENESIS, 1983, 4 (01) :119-121
[3]   CYTOTOXICITY, SISTER-CHROMATID EXCHANGES AND DNA SINGLE-STRAND BREAKS INDUCED BY 4-OXO-4-(3-PYRIDYL)BUTANAL, A METABOLITE OF A TOBACCO-SPECIFIC N-NITROSAMINE [J].
ALAOUIJAMALI, MA ;
GAGNON, R ;
ELALAMI, N ;
CASTONGUAY, A .
MUTATION RESEARCH, 1990, 240 (01) :25-33
[4]   GLUTATHIONE MONOETHYL ESTER - PREPARATION, UPTAKE BY TISSUES, AND CONVERSION TO GLUTATHIONE [J].
ANDERSON, ME ;
POWRIE, F ;
PURI, RN ;
MEISTER, A .
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 1985, 239 (02) :538-548
[5]   CARCINOGENIC NITROSAMINES - FREE-RADICAL ASPECTS OF THEIR ACTION [J].
BARTSCH, H ;
HIETANEN, E ;
MALAVEILLE, C .
FREE RADICAL BIOLOGY AND MEDICINE, 1989, 7 (06) :637-644
[6]  
BELINSKY SA, 1990, CANCER RES, V50, P3772
[7]  
BRADLEY MO, 1982, CANCER RES, V42, P2592
[8]   HYDROGEN-PEROXIDE INSULT IN CULTURED MAMMALIAN-CELLS - RELATIONSHIPS BETWEEN DNA SINGLE-STRAND BREAKAGE, POLY(ADP-RIBOSE) METABOLISM AND CELL KILLING [J].
CANTONI, O ;
CATTABENI, F ;
STOCCHI, V ;
MEYN, RE ;
CERUTTI, P ;
MURRAY, D .
BIOCHIMICA ET BIOPHYSICA ACTA, 1989, 1014 (01) :1-7
[9]   STUDY OF DNA METHYLATION BY TOBACCO-SPECIFIC N-NITROSAMINES [J].
CASTONGUAY, A ;
FOILES, PG ;
TRUSHIN, N ;
HECHT, SS .
ENVIRONMENTAL HEALTH PERSPECTIVES, 1985, 62 (OCT) :197-202
[10]   PROTECTIVE ROLE OF THIOLS IN CARCINOGEN-INDUCED DNA DAMAGE IN RAT-LIVER [J].
CHAN, JYH ;
STOUT, DL ;
BECKER, FF .
CARCINOGENESIS, 1986, 7 (10) :1621-1624