Effects of synthetic and natural in vivo inhibitors of β-glucuronidase on azoxymethane-induced colon carcinogenesis in rats
Effects of synthetic and natural in vivo inhibitors of β-glucuronidase on azoxymethane-induced colon carcinogenesis in rats
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DOI：
10.3892/mmr_00000022
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发表时间：
2008-09-01
影响因子：
3.4
通讯作者：
Yoshimi, Naoki
中科院分区：
文献类型：
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作者：
Morita, Nanae;Walaszek, Zbigniew;Yoshimi, Naoki
D-葡萄糖酸是一种无毒的天然化合物，存在于许多水果和蔬菜中。我们以前的研究表明，D-葡萄糖醛酸酶抑制剂D-葡萄糖-1，4-内酯是D-葡萄糖酸的活性代谢产物，能抑制化学诱导的啮齿动物肿瘤的发生。D-葡萄糖-1，4-内酯有一种合成前体2，5-二O-乙酰基-D-葡萄糖-1，4：6，3-二内酯或醋酸内酯(ACE)，被称为术后预防性药物，以及一种天然前体D-葡萄糖醛酸伽马内酯(GL)。在本研究中，我们首先观察了血管紧张素转换酶(ACE)对15 mg/kg偶氮甲烷(AOM)3次皮下注射诱导大鼠结肠癌形成的影响。在为期5周的短期实验的第1、2和3周注射。给予ACE(0.5%或2%)作为膳食补充，连续5周。治疗5周后，AOM加0.5%和2%ACE饲料组大鼠畸形隐窝灶(ACF)的形成分别比单独AOM组减少48.6%和55.3%。在先前的一项研究中，在AOM治疗期间分配0.5%和2%的ACE饮食有降低AOM诱导的结肠肿瘤发生率的趋势。在目前的长达36周的结肠癌形成实验中，在起始期(从第一次注射AOM前1周开始，第三次注射后1周结束)通过饮食给予GL(0.5%或2%)对肿瘤发生率没有任何显著影响。另一方面，持续使用血管紧张素转换酶(ACE)(0.5%和2%)治疗后，结肠癌发病率分别显著降低了70%和80%。甘草酸的抑制率与此相似(70%)，但仅在2%的浓度下有效。我们的结论是，ACE抑制AOM诱导的结肠癌的起始阶段和启动后阶段，而GL仅影响启动后阶段。
D-Glucaric acid is a non-toxic natural compound found in many fruits and vegetables. Our previous studies have shown that the B-glucuronidase inhibitor D-glucaro-1,4-lactone, an active metabolite of D-glucaric acid, inhibits chemically-induced tumorigenesis in rodents. D-Glucaro-1,4-lactone has a synthetic precursor, 2,5-di-O-acetyl-D-glucaro-1,4:6,3-dilactone or aceglatone (ACE), known as a postoperative prophylactic agent, and a natural precursor, D-glucurono-gamma-lactone (GL). In the present study, we first examined the effect of ACE on the initiation phase of rat colon carcinogenesis induced by 15 mg/kg azoxymethane (AOM) administered 3 times by subcutaneous (s.c.) injection at weeks 1, 2, and 3 of a 5-week short-term experiment. ACE (0.5 or 2%) was administered as a dietary supplement for 5 weeks. At 5 weeks after the initiation of treatment, the formation of aberrant crypt foci (ACF) in the rat groups treated with AOM plus a 0.5 or 2% ACE diet was significantly reduced by 48.6 and 55.3%, respectively, compared to the group administered AOM alone. In a previous study, 0.5 and 2% ACE diets dispensed during AOM treatment had a tendency to decrease AOM-induced colonic tumor incidence. In the present long-terrn 36-week colon tumorigenesis experiment, GL (0.5 or 2%) administered via the diet during the initiation phase (starting 1 week before the first dose of AOM and ending 1 week after the 3rd dose) did not have any significant effects on tumor incidence. On the other hand, continued post-initiation treatment with ACE (0.5 and 2%) markedly reduced colonic tumor incidence by 70 and 80%, respectively. GL was effective to a similar extent (70% inhibition), but only at a concentration of 2%. We conclude that ACE inhibits the initiation and pos-tinitiation stages of AOM-induced colon carcinogenesis, while GL affects only the post-initiation stages.