The catabolism of medium- and long-chain dicarboxylic acids.
The catabolism of medium- and long-chain dicarboxylic acids.
复制标题
中链和长链二羧酸的分解代谢。
DOI：
10.1042/bst0160423
复制
发表时间：
1988
影响因子：
3.9
通讯作者：
Veitch,K
中科院分区：
文献类型：
--
作者：
VanHoof,F;Vamecq,J;Draye,JP;Veitch,K
脂肪酸的w-氧化会导致中链和长链二羧酸盐的形成。通过这一辅助代谢途径，一元酸首先被转化为w-羟基一元酸，这一反应是由微粒体混合氧化酶功能系统催化的(Pettersen，1972)。这些中间体随后在胞质醇脱氢酶和醛脱氢酶的作用下转化为w-氧代单羧酸和二元酸(Mitz&Heinrikson，196 1)。中链二元酸可以由长链二元酸形成，并可在尿液中排泄。这种有机酸尿在各种情况下都会增加，这些情况下脂肪酸降解过度，如酮症和糖尿病，或继发于线粒体脂肪酸氧化缺陷，包括遗传性代谢缺陷、低甘氨酸中毒和核黄素缺乏，以及接受中链三酰甘油的受试者。二元酸可被大鼠肝微体合成酶激活为辅酶A酯(Vamecq et ul，1985)。在氯贝特处理的大鼠中，长链和中链二元酸酯可以被肝脏线粒体和过氧化体部分/3-氧化(Kolvraa&Grcgersen，1986)，而在对照动物中，这种分解代谢主要是过氧体(Vamecq，1987)。因此，我们的研究主要集中在对照、核黄素缺乏和氯贝特治疗的大鼠体内二元酸的分解代谢。此外，还观察了对照组大鼠肝脏线粒体对二羧酸盐的缩短作用。通过以下程序研究了三组动物的十二烷二酸的氧化速率。麻醉的大鼠被插管以直接获得血液，并从膀胱连续收集尿液。十二烷二酸以其钠盐的形式在30分钟内以每100克体重11、22和44pmol的剂量注入。从输液前1h至输液后3h，在30min内收集尿液。提取有机酸，并使用Intersmat IGC-12 1 DC气相色谱仪(法国Suresnes)与Intersmat ICR-1B积分器连接并配备如上所述的50 m毛细管柱(直径0.32 mm，Chrompack CP Sill 5熔融硅胶)，通过气相色谱分离和检测三甲基硅烷基衍生物(Draye等人，1987)。在对照组和核黄素缺乏的大鼠中，十二烷二酸(22pmo1/100g体重)迅速转化为己二酸、琥珀酸和二十二酸，出现在尿液中(图3)。i)。琥珀酸的排泄量仍然很低，而且不会因输液而改变。在对照动物中，这个过程持续不到2小时，尿二元酸占给药剂量的28.6±1.0%(平均f扫描电子显微镜；11=4)。超过60%的这种排泄发生在输液期后30分钟内。核黄素缺乏大鼠的尿二元酸排泄量占输注量的75.6k15.5%(n=3)，输注后3h尿液中二元酸排泄率为75.6%。在氯贝特处理的大鼠中，尿中十二烷二酸仅以较短的二元酸形式被回收4.4±1.2%(n=3)。根据中链二元酸在尿液中的初始出现率计算出的二元酸的最大表观氧化速度在对照组和核黄素缺乏的动物中相似。这一P-氧化速率相当于对照组每100克体重形成10.0pmoL乙酰辅酶A/30分钟，而核黄素缺乏啮齿动物每100克体重形成14.8 pmol/30分钟乙酰辅酶A。当以…的百分比表示时，后一组动物的肝脏比对照组大1.4倍
The w-oxidation of fatty acids results in the formation of medium-and long-chain dicarboxylates. By this accessory metabolic pathway monocarboxylic acids are first converted into w-hydroxymonocarboxylic acids, a reaction catalysed by the microsomal mixed-oxidase function system (Pettersen, 1972). These intermediates are subsequently converted into w-oxomonocarboxylic acids and dicarboxylic acids by the action of cytosolic alcohol-and aldehyde-dehydrogenases (Mitz & Heinrikson, 196 1). Medium-chain dicarboxylic acids can be formed from long-chain dicarboxylic acids and be excreted in urine. This organic aciduria is increased in a variety of conditions with excessive fatty acid degradation such as ketosis and diabetes mellitus or secondarily to defective mitochondrial fatty acid oxidation, including inherited metabolic defects, hypoglycin intoxication and riboflavin deficiency, as well as in subjects receiving medium-chain triacylglycerols. Dicarboxylic acids can be activated to their CoA esters by a rat liver microsomal synthetase (Vamecq et ul., 1985). In clofibrate-treated rats, esters of long-and medium-chain dicarboxylic acids can be/3-oxidized by both liver mitochondrial and peroxisomal fractions (Kolvraa & Grcgersen, 1986), whereas in control animals this catabolism is mainly peroxisomal (Vamecq, 1987). Our studies were thus mainly dedicated to the catabolism of dicarboxylic acids in control, riboflavin-deficient and clofibrate-treated rats in vivo. The shortening of dicarboxylates by isolated mitochondria from the livers of control rats was also investigated. Thc rate of oxidation of dodecanedioic acid was studied in the three groups of animals by the following procedure. Anaesthetized rats were cannulated to give direct access to blood, and urine was continuously collected from the bladder. Dodecanedioic acid was infused in the form of its Na salt in doses of 11, 22 and 44 pmol per 100 g body weight during a 30 min period. Urine was collected over 30 min periods from 1 h before to 3 h after infusion. Organic acids were extracted, and trimethylsilylated derivatives were separated and detected by gas chromatography using an Intersmat IGC-12 1 DC gas chromatograph (Suresnes, France) coupled to an Intersmat ICR-1B integrator and equipped with a 50 m capillary column (0.32 mm in diameter, Chrompack CP Sil 5 fused silica) as previously described (Draye et ul., 1987). In control and riboflavin-deficient rats, dodecanedioic acid (22 pmo1/100 g body weight) was rapidly transformed into adipic, suberic and sebacic acids, which appeared in urine (Fig. I). Excretion of succinic acid remained low and was not modified by the infusion. In control animals, this process lasted less than 2 h, and urinary dicarboxylic acids amounted to 28.6 f 1.0%(mean f SEM; 11= 4) of the dose administered. Over 60"% of this excretion occurred within 30 min after the infusion period. In riboflavin-deficient rats, the process was slower and not complete 3 h after infusion; dicarboxylic acids in urine amounted to 75.6 k 15.5%(n= 3) of the infused dose. In clofibrate-treated rats, only 4.4 f 1.2%(n= 3) of dodecanedioic acid was recovered as shorter dicarboxylic acids in urine.The maximal apparent velocity of dicarboxylate oxidation as calculated from the initial rate of appearance of mediumchain dicarboxylic acids in urine is similar in control and riboflavin-deficient animals. This rate of P-oxidation corresponds to the formation of 10.0 pmol of acetyl-CoA/30 min per 100 g body weight in controls, and 14.8 pmol/30 min per 100 g body weight in riboflavin-deficient rodents. The livers of the latter animals were 1.4 times larger than those of controls, when expressed as a percentage of …