Allegri Graziella, Ragazzi Eugenio, Costa Carlo V L, Caparrotta Laura, Biasiolo Monica, Comai Stefano, Bertazzo Antonella
Department of Pharmaceutical Sciences, University of Padova, Via F. Marzolo 5, I-35131 Padova, Italy.
Clin Chim Acta. 2004 Dec;350(1-2):41-9. doi: 10.1016/j.cccn.2004.06.026.
The activity of nicotinic acid in hypercholesterolemia has been poorly understood. In man, nicotinic acid derives for the most part from tryptophan along the tryptophan-nicotinic acid pathway, also called the kynurenine pathway, kynurenine being the key metabolite in this process. In the present paper, we investigated if, in animals with hypercolesterolemia, degradation of tryptophan to nicotinic acid along the kynurenine pathway was perturbated.
Liver, kidney and intestine enzyme activities of the tryptophan-nicotinic acid pathway in normolipidemic, diet-induced hyperlipidemic New Zealand and heritable hypercholesterolemic Watanabe (WHHL) rabbits were determined.
Liver tryptophan 2,3-dioxygenase (TDO) activity was present only as a holoenzyme and was higher in the controls than in the hyperlipidemic and Watanabe rabbits, but no difference was present between the group fed an atherogenic hyperlipidic diet and the WHHL rabbits. Small intestine indole 2,3-dioxygenase (IDO) did not vary significantly among the three groups but was higher in comparison with liver TDO activity. In liver, kynurenine 3-monooxygenase and kynurenine-oxoglutarate transaminase activities did not show any significant difference among the three groups of rabbits. Kynureninase and 3-hydroxyanthranilate 3,4-dioxygenase activities per g of fresh tissue decreased significantly in the group of hyperlipidemic and in WHHL rabbits. In the kidneys, kynurenine 3-monooxygenase and kynureninase activity did not change significantly in the three groups of rabbits; kynurenine-oxoglutarate transaminase activity per g of fresh tissue decreased in both hyperlipidemic groups, but no significant difference was observed between hyperlipidemic and Watanabe rabbits. 3-Hydroxyanthranilate 3,4-dioxygenase activity in kidney was decreased markedly in hyperlipidemic and Watanabe rabbits, but there was no difference between the two hypercholesterolemic groups. Aminocarboxymuconate-semialdehyde decarboxylase activity did not change. Thus 3-hydroxyanthranilate 3,4-dioxygenase may be an important regulatory mechanism in the control of the flow of tryptophan along the kynurenine pathway to NAD in hypercholesterolemic rabbits.
This study first demonstrates that in rabbits, hypercholesterolemia, both diet- or genetically induced, can influence the enzyme activities of the tryptophan-nicotinic acid pathway leading to a decreased formation of nicotinic acid, and thus NAD.
烟酸在高胆固醇血症中的作用一直未被充分了解。在人体中，烟酸大部分沿色氨酸-烟酸途径（也称为犬尿氨酸途径）由色氨酸生成，犬尿氨酸是此过程中的关键代谢产物。在本文中，我们研究了在高胆固醇血症动物中，色氨酸沿犬尿氨酸途径向烟酸的降解是否受到干扰。
测定了正常血脂、饮食诱导的高脂血症新西兰兔以及遗传性高胆固醇血症渡边（WHHL）兔色氨酸-烟酸途径的肝脏、肾脏和肠道酶活性。
肝脏色氨酸2,3-双加氧酶（TDO）仅以全酶形式存在，其活性在对照组中高于高脂血症兔和渡边兔，但致动脉粥样硬化高脂饮食组与WHHL兔之间无差异。小肠吲哚2,3-双加氧酶（IDO）在三组中无显著差异，但与肝脏TDO活性相比更高。在肝脏中，犬尿氨酸3-单加氧酶和犬尿氨酸-氧代戊二酸转氨酶活性在三组兔中均无显著差异。每克新鲜组织中的犬尿氨酸酶和3-羟基邻氨基苯甲酸3,4-双加氧酶活性在高脂血症组和WHHL兔中显著降低。在肾脏中，犬尿氨酸3-单加氧酶和犬尿氨酸酶活性在三组兔中无显著变化；每克新鲜组织中的犬尿氨酸-氧代戊二酸转氨酶活性在两个高脂血症组中均降低，但高脂血症兔与渡边兔之间无显著差异。高脂血症兔和渡边兔肾脏中的3-羟基邻氨基苯甲酸3,4-双加氧酶活性显著降低，但两个高胆固醇血症组之间无差异。氨基羧基粘康酸-半醛脱羧酶活性无变化。因此，3-羟基邻氨基苯甲酸3,4-双加氧酶可能是高胆固醇血症兔中控制色氨酸沿犬尿氨酸途径向烟酰胺腺嘌呤二核苷酸（NAD）流动的重要调节机制。
本研究首次证明，在兔中，饮食诱导或遗传诱导的高胆固醇血症均可影响色氨酸-烟酸途径的酶活性，导致烟酸生成减少，进而使NAD生成减少。
