GlutathioneS-Transferases of Female A/J Mouse Lung and Their Induction by Anticarcinogenic Organosulfides from Garlic

Abstract

GlutathioneS-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-7β,8α-dihydroxy9α,10α-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene [(+)-antiBPDE], 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 α class (pI9.4 and 6.0), two μ class (pI8.7 and 8.6), and one π class (pI8.9) 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 α class heterodimeric isoenzyme (pI9.5) 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 π 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 π 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 π type GST in the lung than in the forestomach by these OSCs.