Potentiation of benzo[a]pyrene-induced pulmonary and forestomach tumorigenesis in mice by D,L-buthionine-S,R-sulfoximine-mediated tissue glutathione depletion.
In vitro studies have suggested that the glutathione (GSH) S-transferase (GST)-catalyzed GSH conjugation is an important mechanism for the detoxification of (+)-anti-7,8-dihydroxy-9, 10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene [(+)-anti-BPDE], which is the activated form of the widespread environmental pollutant benzo[a]pyrene (BP). However, in vivo experimental evidence for the importance of GSH/GST system in defense against carcinogenic effects of BP is lacking. We hypothesized that if GSH/GST were to play an important role in the detoxification of (+)-anti-BPDE, the tumorigenic activity of BP would be increased by depleting the levels of GSH, which is the required nucleophilic substrate for GST-catalyzed conjugation reactions. In the present study, we have tested the above hypothesis by determining the effect of D, L-buthionine-S,R-sulfoximine (BSO)-mediated tissue GSH depletion on BP-induced tumorigenesis of the lung and forestomach in female A/J mice. Treatment of mice with three i.p. injections of 2.5 mmol BSO/kg (12 h apart) plus 20 mM BSO in drinking water, resulted in a statistically significant reduction in hepatic, pulmonary and forestomach GSH levels. At the same time, BSO-administration caused a statistically significant increase in BP-induced pulmonary and forestomach tumor multiplicity. To the best of our knowledge, the present study is the first report that provides in vivo experimental evidence for the importance of GSH/GST system in cellular protection against carcinogenic effects of BP.
Srivastava
S K
SK
Cancer Research Laboratory, Mercy Hospital, 1400 Locust Street, Pittsburgh, PA 15219, USA.
Xia
H
H
Pal
A
A
Hu
X
X
Guo
J
J
Singh
S V
SV
D000818:Animals; D000963:Antimetabolites / Q000633:toxicity; D001564:Benzo(a)pyrene / Q000633:toxicity*; D019328:Buthionine Sulfoximine / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity; D004357:Drug Synergism; D005260:Female; D005978:Glutathione / Q000378:metabolism*; D008175:Lung Neoplasms / Q000139:chemically induced*; D051379:Mice; D013274:Stomach Neoplasms / Q000139:chemically induced*
D000963:Antimetabolites; D002273:Carcinogens; D001564:Benzo(a)pyrene; D019328:Buthionine Sulfoximine; D005978:Glutathione