Cascales M, Martín-Sanz P, Craciunescu D G, Mayo I, Aguilar A, Robles-Chillida E M, Cascales C
Instituto de Bioquimica (CSIC-UCM), Facultad de Farmacia, Universidad Complutense, Madrid, Spain.
Carcinogenesis. 1991 Feb;12(2):233-40. doi: 10.1093/carcin/12.2.233.
A model of liver hyperplastic noduligenesis was induced in rats in vivo by long-term administration of thioacetamide (TAM; 100 mg/kg day i.p.). Three doses of 50 mg/kg of an antitumoral rhodium(III) complex were administered at 14, 9 and 5 days before the end of TAM treatment. Blood and liver were obtained from either TAM, Rh(III) complex or TAM plus Rh(III) complex-treated rats in order to determine the interaction of both (tumoral and antitumoral) substances with the biochemical pathways related to glutathione redox cycle, enzyme activities involved in the oxidative stress coupled to the NADPH/NADP pair and enzymes related to the mono-oxygenase P450 system. The results showed that TAM induced an imbalance between the activities of glutathione-coupled enzymes. Glutathione reductase activity increased along with the intoxication, while glutathione peroxidase activity decreased. Alterations in the activity of soluble glutathione peroxidase were parallel to those of catalase. These results, together with decreased activities of enzymes related to cytochrome P450 mono-oxygenase system, NADPH cytochrome P450 reductase and NADH cytochrome b5 reductase, suggest that liver cells are not protected against the peroxidative stress produced by chronic administration of TAM. The Rh(III) complex did not produce significant changes in the parameters assayed when administered alone. When this complex was administered to TAM-treated rats, significant restoration of the following activities was observed: those of NADPH-generating enzymes (glucose-6-phosphate dehydrogenase and malic enzyme), that of glutathione reductase (NADPH-consuming enzyme), NADPH-cytochrome P450 reductase and total catalase. These results, together with others in previous studies, suggest that the altered liver function induced by chronic administration of TAM can be partially restored by this rhodium complex. The mechanisms by which this complex counteracts the TAM-induced changes have not yet been established.
通过长期腹腔注射硫代乙酰胺（TAM；100 mg/kg/天）在大鼠体内诱导肝增生性结节形成模型。在TAM治疗结束前14天、9天和5天分别给予三剂50 mg/kg的抗肿瘤铑（III）配合物。从接受TAM、铑（III）配合物或TAM加铑（III）配合物治疗的大鼠中获取血液和肝脏，以确定这两种（肿瘤和抗肿瘤）物质与谷胱甘肽氧化还原循环相关生化途径、与NADPH/NADP对偶联的氧化应激相关酶活性以及与单加氧酶P450系统相关酶之间的相互作用。结果表明，TAM诱导了谷胱甘肽偶联酶活性之间的失衡。随着中毒程度加重，谷胱甘肽还原酶活性增加，而谷胱甘肽过氧化物酶活性降低。可溶性谷胱甘肽过氧化物酶活性的变化与过氧化氢酶的变化平行。这些结果，连同细胞色素P450单加氧酶系统、NADPH细胞色素P450还原酶和NADH细胞色素b5还原酶相关酶活性的降低，表明肝细胞不能抵御长期给予TAM所产生的过氧化应激。单独给予铑（III）配合物时，所检测的参数未产生显著变化。当将该配合物给予TAM处理的大鼠时，观察到以下活性有显著恢复：产生NADPH的酶（葡萄糖-6-磷酸脱氢酶和苹果酸酶）、谷胱甘肽还原酶（消耗NADPH的酶）、NADPH-细胞色素P450还原酶和总过氧化氢酶的活性。这些结果，连同先前研究中的其他结果，表明该铑配合物可部分恢复长期给予TAM所诱导的肝功能改变。该配合物抵消TAM诱导变化的机制尚未明确。
