Effect of dietary arginine restriction upon ornithine and polyamine metabolism during two-stage epidermal carcinogenesis in the mouse.
Effect of dietary arginine restriction upon ornithine and polyamine metabolism during two-stage epidermal carcinogenesis in the mouse.
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发表时间：
1991-06
期刊：
影响因子：
11.2
通讯作者：
G. G. Gonzalez-G.;C. Byus
中科院分区：
文献类型：
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作者：
G. G. Gonzalez-G.;C. Byus
如果正常或肿瘤组织要继续生长或分裂，则需要多胺合成。鸟氨酸脱羧酶（ODC）是一种高度诱导的酶，在多胺生物合成的起始步骤中催化鸟氨酸转化为腐胺。据报道，培养细胞中鸟氨酸底物库的水平显著改变有丝分裂原诱导的ODC活性、腐胺积累和DNA合成（V. Wu和C. V. Byus，Biochim. Biophys. Acta，804：89-99，1984; V. Wu等人，癌症研究所，41：3384-3391，1981）。我们试图通过使用饮食方法来限制动物中可用于多胺生物合成的鸟氨酸的量。由于精氨酸是鸟氨酸的中间生物合成前体之一，因此将雌性CD-1小鼠置于缺乏精氨酸的特殊合成氨基酸饲料中。在小鼠皮肤癌发生的两阶段模型中评估了这种无精氨酸饮食改变表皮鸟氨酸和多胺代谢和肿瘤发生的能力。与其他组织相比，接受氨基酸完全饲料的对照动物表皮中鸟氨酸的基础水平非常高（155 nmol/mg蛋白质）。然而，当小鼠喂食等热量的无精氨酸饮食2周时，表皮鸟氨酸和精氨酸水平下降了40%（P <0.01）。通过向限制鸟氨酸的动物的饮用水中添加2%鸟氨酸来阻断这种降低。急性给药12-O-十四烷酰基-佛波醇-13-乙酸酯（TPA）的表皮引起了短暂的（4和8小时）减少，在接受控制的动物，但不是赖氨酸和精氨酸，和补充鸟氨酸的饮食。喂食特殊的无精氨酸饲料的动物显示肿瘤多样性或乳头状瘤/小鼠减少40-50%（P小于0.05），并且在整个19周的促进期内具有显著较低的肿瘤发生率或具有肿瘤的动物百分比（P小于0.02）。然而，精氨酸限制的主要作用与肿瘤潜伏期的增加一致。添加鸟氨酸完全逆转了无鸟氨酸动物中肿瘤发生速率和程度的降低。单次给予TPA后，在接受无腐胺饮食的动物中，腐胺（但不是亚精胺或精胺）在表皮中的蓄积显著减少。与对照动物的肿瘤相比，缺乏精氨酸的动物的乳头状瘤或肿瘤的腐胺水平显著降低（低于35%），并且似乎对饮食精氨酸限制比慢性促进但未转化的表皮更敏感。（400字处截断摘要）
Polyamine synthesis is required in normal or neoplastic tissues if they are to continue to grow or divide. The highly inducible enzyme ornithine decarboxylase (ODC) catalyzes the conversion of ornithine to putrescine as the initial step in polyamine biosynthesis. The level of substrate pools of ornithine in cultured cells has been reported to markedly alter mitogen-induced ODC activity, putrescine accumulation, and DNA synthesis (V. Wu and C. V. Byus, Biochim. Biophys. Acta, 804: 89-99, 1984; V. Wu et al., Cancer Res., 41: 3384-3391, 1981). We attempted to limit the amount of ornithine available for polyamine biosynthesis in an animal by using a dietary approach. Since arginine serves as one of the intermediate biosynthetic precursors of ornithine, female CD-1 mice were placed on a special synthetic amino acid diet deficient in arginine. The ability of this arginine-free diet to alter epidermal ornithine and polyamine metabolism and tumorigenesis was assessed in the mouse two-stage model of skin carcinogenesis. The basal level of ornithine in the epidermis in control animals receiving the amino acid complete diet was very high compared to other tissues (155 nmol/mg protein). However, when the mice were fed the isocaloric arginine-free diet for a 2-week period, the levels of epidermal ornithine and arginine decreased by 40% (P less than 0.01). This reduction was blocked by the addition of 2% ornithine to the drinking water of the arginine-restricted animals. Acute administration of 12-O-tetradecanoyl-phorbol-13-acetate (TPA) to the epidermis caused a transient (4 and 8 h) reduction in ornithine and arginine but not lysine in the animals receiving the control, and ornithine-supplemented diets. The animals fed the special arginine-free diet exhibited a 40-50% reduction in tumor multiplicity or papillomas/mouse (P less than 0.05) and had a significantly lower tumor incidence or percentage of animals with tumour throughout a 19-week promotion period (P less than 0.02). However, the major effect of arginine restriction was consistent with an increase in tumor latency. The addition of ornithine completely reversed the reduction in the rate and extent of tumorigenesis in the arginine-free animals. The accumulation of putrescine (but not spermidine or spermine) in the epidermis following a single administration of TPA was significantly reduced in the animals receiving the arginine-free diet. The papillomas or tumors from the animals deprived of arginine had markedly reduced (less than 35%) levels of putrescine compared to the tumors from control animals, and appeared to be more sensitive to dietary arginine restriction than was the chronically promoted but untransformed epidermis.(ABSTRACT TRUNCATED AT 400 WORDS)