Glutathione S-transferases of female A/J mouse lung and their induction by anticarcinogenic organosulfides from garlic.
Glutathione S-transferases (GSTs) of female A/J mouse lung have been purified and characterized for their (a) structural interrelationships, (b) substrate specificities toward the ultimate carcinogenic metabolite of benzo(a)pyrene (BP), (+)-anti-7 beta, 8 alpha-dihydroxy-9 alpha, 10 alpha-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene [(+)-anti-BPDE], and (c) induction by three naturally occurring organosulfides (OSCs)-from garlic [diallyl sulfide (DAS), diallyl trisulfide (DATS) and dipropyl sulfide (DPS)], which significantly differ in their efficacy against BP-induced lung cancer in mice. The GST activity in the lung was due to two alpha class (pI 9.4 and 6.0), two mu class (pI 8.7 and 8.6), and one pi class (pI 8.9) isoenzyme. The GST isoenzyme profile of the lung was different from that of the A/J mouse forestomach, which also is a target organ for BP-induced cancer in mice. Noticeably, an alpha class heterodimeric isoenzyme (pI 9.5) present in the forestomach of A/J mouse, which is exceptionally efficient in the glutathione (GSH) conjugation of (+)-anti-BPDE [X. Hu, S.K. Srivastava, H. Xia, Y. C. Awasthi, and S. V. Singh (1996) J. Biol. Chem. 271, 32684-32688], could not be detected in the lung. The specific activities of the lung GSTs in the GSH conjugation of (+)-anti-BPDE were in the order of GST 8.9 > GST 8.7 > GST 9.4 > GST 6.0. While DPS treatment did not increase the levels of any pulmonary GST isoenzyme, the expression of pi class GST 8.9 was significantly increased in response to both DAS and DATS administrations. Interestingly, DATS, an OSC which lacks activity against BP-induced lung cancer in mice, was a relatively more potent inducer of pi class GST isoenzyme than DAS, which is a potent inhibitor of BP-induced lung tumorigenesis. The results of the present study suggest that a mechanism(s) other than GST induction is likely to be responsible for the differential effects of DAS and DATS on BP-induced lung cancer in mice. Our results also suggest that relatively lower efficacies of the OSCs against BP-induced lung cancer than against forestomach neoplasia may be attributed to (a) a lack of expression in the lung of an isoenzyme corresponding to forestomach GST 9.5 and (b) a comparatively lower level of induction of pi type GST in the lung than in the forestomach by these OSCs.
Hu
X
X
Cancer Research Laboratory, Mercy Cancer Institute, Mercy Hospital of Pittsburgh, Pennsylvania 15219, USA.
Singh
S V
SV
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000378:metabolism*; D000498:Allyl Compounds / Q000494:pharmacology*; D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D005737:Garlic / Q000737:chemistry*; D005982:Glutathione Transferase / Q000096:biosynthesis* / Q000737:chemistry; D007527:Isoenzymes / Q000096:biosynthesis; D008168:Lung / Q000201:enzymology*; D008175:Lung Neoplasms / Q000139:chemically induced / Q000517:prevention & control; D051379:Mice; D008805:Mice, Inbred A; D008969:Molecular Sequence Data; D010946:Plants, Medicinal; D011407:Propane / Q000031:analogs & derivatives* / Q000494:pharmacology; D013440:Sulfides / Q000494:pharmacology*
D000498:Allyl Compounds; D007527:Isoenzymes; D013440:Sulfides; C042577:diallyl trisulfide; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; C038491:allyl sulfide; D005982:Glutathione Transferase; C087894:dipropyl sulfide; D011407:Propane