Glutathione S-transferases of female A/J mouse liver and forestomach and their differential induction by anti-carcinogenic organosulfides from garlic
Glutathione S-transferases of female A/J mouse liver and forestomach and their differential induction by anti-carcinogenic organosulfides from garlic
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DOI：
10.1006/abbi.1996.0550
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发表时间：
1996-12-15
影响因子：
3.9
通讯作者：
Singh, SV
中科院分区：
文献类型：
--
作者：
Hu, X;Benson, PJ;Singh, SV
本研究表征了雌性A/J小鼠肝脏和前胃的谷胱甘肽（GSH）S-转移酶（GST）同工酶，并比较了它们在催化GSH与苯并[a]芘（BP）的最终致癌代谢物7 β，8 α-二羟基-9 α，10 α-氧-7，8，9，10-四氢苯并[a]芘（抗BPDE）结合方面的特异性。雌性A/J小鼠肝脏中的GST活性由至少7种同工酶表达，这些同工酶来自至少2种α类（指定为α 1和α 4）、4种μ类（μ 1至μ 4）和1种pi类GST亚基的不同同源或异源二聚体组合。A/J小鼠前胃GST同工酶组成与肝脏不同。例如，虽然含有μ 3和μ 4型亚基的GST同工酶在肝脏中选择性表达，但α类异二聚体GST同工酶（含有α 2和α 3亚基）在前胃中表达，但在肝脏中无法检测到。除了含有α 4型GST亚基的同工酶外，对于所有GST，（+）-抗BPDE似乎是比（-）-对映体更好的底物。小鼠α类GST同工酶对（+）-anti-BPDE的特异性较其它GST高，对（+）-anti-BPDE的特异性大小顺序为pi > mu > alpha。这些结果表明，类GST同工酶可能在提供对BP诱导的癌症的保护中发挥重要作用。因此，假设化学保护剂增加GST π表达的能力可能是其对抗BP诱导的癌症的有效性的重要决定因素似乎是合乎逻辑的。为了验证这一论点的有效性，我们已经确定了对肝脏和前胃GST同工酶/亚基表达的三种天然存在的有机硫化物（OSC）大蒜，显着不同的有效性对BP诱导的前胃癌的影响。用二烯丙基硫醚（DAS）和二烯丙基三硫醚（DATS）治疗小鼠，这是BP诱导的小鼠前胃癌的有效抑制剂，导致肝脏和前胃GST抗BPDE活性显著增加。与此相反，这种活性并没有增加，在任何一个器官的二丙基硫醚（DPS），这是无效的对BP诱导的前胃癌。这些OSC的化学预防功效与它们增加GST pi表达的能力相关。例如，DAS处理导致肝和前胃GST pi表达分别比对照增加约1.7倍和2.2倍。用DATS（其是比DAS相对更有效的BP诱导的前胃癌抑制剂）治疗小鼠，导致肝和前胃GST pi表达分别比对照增加约3.8倍和3.2倍。相反，DPS给药后，肝和前胃GST pi的表达仅略微增加（10-20%）。总之，本研究的结果表明，GST pi的诱导可用作筛选BP诱导的癌症的潜在抑制剂的生物测定。(C)出版社：Academic Press，Inc.
This study characterizes glutathione (GSH) S-transferase (GST) isoenzymes of the liver and forestomach of the female A/J mouse and compares their specificities in catalyzing the conjugation of GSH with 7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene (anti-BPDE), the ultimate carcinogenic metabolite of benzo[a]pyrene (BP). The GST activity in female A/J mouse liver was expressed by a minimum of seven isoenzymes which arose from different homoor heterodimeric combinations of at least two alpha class (designated as alpha 1 and alpha 4), four mu class (mu 1 to mu 4), and one pi class GST subunit. The GST isoenzyme composition of A/J mouse forestomach appeared to be different from that of the liver. For example, while GST isoenzymes containing mu 3 and mu 4 type subunits were selectively expressed in the liver, an alpha class heterodimeric GST isoenzyme (containing alpha 2 and alpha 3 subunits) was expressed in the forestomach but could not be detected in the liver. The (+)-anti-BPDE appeared to be a better substrate than the (-)-enantiomer for all GSTs, except for isoenzymes containing the alpha 4 type GST subunit. The murine a class GST isoenzyme displayed relativey higher specific activity toward (+)-anti-BPDE compared to other GSTs, The specific activities of mouse GSTs toward (+)-anti-BPDE were in the order of pi > mu > alpha. These results suggest that the a class GST isoenzyme may play an important role in providing protection against BP-induced cancer. Therefore, it seems logical to postulate that the ability of a chemoprotector to increase the expression of GST pi may be an important determinant of its effectiveness against BP-induced cancer. To test the validity of this contention, we have determined the effects on hepatic and forestomach GST isoenzyme/subunit expression of three naturally occurring organosulfides (OSCs) from garlic, which significantly differ in their effectiveness against BP-induced forestomach cancer. Treatment of mice with diallyl sulfide (DAS) and diallyl trisulfide (DATS), which are potent inhibitors of BP-induced forestomach cancer in mice, resulted in a significant increase in hepatic and forestomach GST activity toward anti-BPDE. On the contrary, this activity was not increased in either organ by dipropyl sulfide (DPS), which is ineffective against BP-induced forestomach cancer. The chemopreventive efficacy of these OSCs correlated with their ability to increase the expression of GST pi. For example, DAS treatment resulted in approximate increases of 1.7- and 2.2-fold in hepatic and forestomach GST pi expression, respectively, over the control. Treatment of mice with DATS, which is a relatively more potent inhibitor of BP-induced forestomach cancer than DAS, resulted in about 3.8- and 3.2-fold increases, respectively, in hepatic and forestomach GST pi expression over the control. On the contrary, the expression of hepatic and forestomach GST pi was increased only marginally (10-20%) upon DPS administration. In conclusion, the results of the present study suggest that induction of GST pi can be used as a bioassay for screening potential inhibitors of BP-induced cancer. (C) 1996 Academic Press, Inc.