Aarsland A, Berge R K
Laboratory of Clinical Biochemistry, University of Bergen, Haukeland Sykehus, Norway.
Biochem Pharmacol. 1991 Jan 1;41(1):53-61. doi: 10.1016/0006-2952(91)90010-3.
In liver homogenates from untreated rats the sulphur-substituted fatty acid analogues tetradecylthioacetic acid (CMTTD) was activated to its acyl-coenzyme A thioester. The activation was found to take place in the mitochondrial, microsomal and peroxisomal fractions. The activity of CMTTD-CoA synthetase was 50% compared to palmitoyl-CoA synthetase in all cellular fractions. When rats were treated with the peroxisome proliferating sulphur-substituted fatty acid analogues CMTTD and 3-dithiahexadecanedioic acid (BCMTD), the CMTTD-CoA synthetase activity was induced in mitochondrial, peroxisomal and microsomal fractions. Palmitoyl-CoA synthetase was induced proportionally. In rats treated with tetradecylthiopropionic acid (CETTD) of low peroxisome proliferating potency, the activities of CMTTD-CoA synthetase and palmitoyl-CoA synthetase were inhibited in mitochondrial and microsomal fractions. In contrast, all three sulphur-substituted acids induced the activity of palmitoyl-CoA synthetase and CMTTD-CoA synthetase in peroxisomes. Both the CMTTD-CoA and palmitoyl-CoA synthetase activities were induced by CMTTD and BCMTD, in close correlation to the induction of peroxisomal beta-oxidation. During the three treatment regimes, CMTTD-CoA synthetase activity ran parallel to the palmitoyl-CoA synthetase activity at a rate of 50% in all cellular fractions. Thus, CMTTD is assumed to be activated by the long-chain acyl-CoA synthetase enzyme. Rats were treated for 5 days with sulphur- and oxy-substituted fatty acid analogues, clofibric acid and fenofibric acid. All compounds which induced peroxisomal beta-oxidation activity in vivo could be activated to their respective CoA thioesters in liver homogenate. CETTD which induced peroxisomal beta-oxidation only two-fold, was activated at a rate of 50% compared to palmitate. Fenofibric acid induced peroxisomal beta-oxidation 9.6-fold, while it was activated at a rate of only 10% compared to palmitate. Thus, no correlation was found between rate of activation in vitro and induction of peroxisomal activity in vivo. On the other hand, tetradecylsulfoxyacetic acid (TSOA) and tetradecylsulfonacetic acid (TSA) (sulphuroxygenated metabolites of CMTTD) with no inductive effects, were not activated to their respective CoA derivatives. Altogether the data suggest that the enzymatic activation of the peroxisome proliferating compounds is essential for their proliferating activity, but the rate of activation does not determine the potency of the proliferators. The role of the xenobiotic-CoA pool in relation to the whole coenzyme A profile during peroxisome proliferation is discussed.
在未处理大鼠的肝脏匀浆中，硫取代脂肪酸类似物十四烷基硫代乙酸（CMTTD）被激活为其酰基辅酶A硫酯。发现这种激活发生在线粒体、微粒体和过氧化物酶体部分。在所有细胞部分中，CMTTD-CoA合成酶的活性相对于棕榈酰-CoA合成酶为50%。当用诱导过氧化物酶体增殖的硫取代脂肪酸类似物CMTTD和3-二硫代十六烷二酸（BCMTD）处理大鼠时，线粒体、过氧化物酶体和微粒体部分的CMTTD-CoA合成酶活性被诱导。棕榈酰-CoA合成酶也相应地被诱导。在用过氧化物酶体增殖能力低的十四烷基硫代丙酸（CETTD）处理的大鼠中，线粒体和微粒体部分的CMTTD-CoA合成酶和棕榈酰-CoA合成酶的活性受到抑制。相反，所有三种硫取代酸都诱导过氧化物酶体中棕榈酰-CoA合成酶和CMTTD-CoA合成酶的活性。CMTTD-CoA和棕榈酰-CoA合成酶的活性都被CMTTD和BCMTD诱导，与过氧化物酶体β-氧化的诱导密切相关。在三种处理方案中，所有细胞部分的CMTTD-CoA合成酶活性与棕榈酰-CoA合成酶活性以50%的比例平行。因此，推测CMTTD被长链酰基辅酶A合成酶激活。用硫和氧取代的脂肪酸类似物、氯贝酸和非诺贝特酸处理大鼠5天。所有在体内诱导过氧化物酶体β-氧化活性的化合物在肝脏匀浆中都能被激活为各自的CoA硫酯。仅诱导过氧化物酶体β-氧化两倍的CETTD，与棕榈酸相比，其激活率为50%。非诺贝特酸诱导过氧化物酶体β-氧化9.6倍，而与棕榈酸相比，其激活率仅为10%。因此，未发现体外激活率与体内过氧化物酶体活性诱导之间的相关性。另一方面，没有诱导作用的十四烷基磺氧基乙酸（TSOA）和十四烷基磺基乙酸（TSA）（CMTTD的硫氧化代谢物）未被激活为各自的CoA衍生物。总之，数据表明过氧化物酶体增殖化合物的酶促激活对其增殖活性至关重要，但激活率并不决定增殖剂的效力。讨论了异生素-CoA库在过氧化物酶体增殖过程中与整个辅酶A谱的关系。
