Laboratorio de Disturbios Metabólicos por Xenobióticos, Salud Humana y Medio Ambiente, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pab. II, 4to Piso, C1428EGA Ciudad Autónoma de Buenos Aires, Argentina.
Toxicology. 2011 Nov 28;290(1):22-30. doi: 10.1016/j.tox.2011.08.014. Epub 2011 Aug 26.
This work deals with the study of how porphyrinogenic drugs modeling acute porphyrias interfere with the status of carbohydrate-regulating hormones in relation to key glucose enzymes and to porphyria, considering that glucose modulates the development of the disease. Female Wistar rats were treated with 2-allyl-2-isopropylacetamide (AIA) and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) using different doses of AIA (100, 250 and 500mg/kg body weight) and a single dose of DDC (50mg DDC/kg body weight). Rats were sacrificed 16h after AIA/DDC administration. In the group treated with the highest dose of AIA (group H), hepatic 5-aminolevulinic acid synthase (ALA-S) increased more than 300%, phosphoenolpyruvate carboxykinase (PEPCK) and glycogen phosphorylase (GP) activities were 43% and 46% lower than the controls, respectively, plasmatic insulin levels exceeded normal values by 617%, and plasmatic glucocorticoids (GC) decreased 20%. GC results are related to a decrease in corticosterone (CORT) adrenal production (33%) and a significant reduction in its metabolization by UDP-glucuronosyltransferase (UGT) (62%). Adrenocorticotropic hormone (ACTH) stimulated adrenal production 3-fold and drugs did not alter this process. Thus, porphyria-inducing drugs AIA and DDC dramatically altered the status of hormones that regulate carbohydrate metabolism increasing insulin levels and reducing GC production, metabolization and plasmatic levels. In this acute porphyria model, gluconeogenic and glycogenolytic blockages caused by PEPCK and GP depressed activities, respectively, would be mainly a consequence of the negative regulatory action of insulin on these enzymes. GC could also contribute to PEPCK blockage both because they were depressed by the treatment and because they are positive effectors on PEPCK. These disturbances in carbohydrates and their regulation, through ALA-S de-repression, would enhance the porphyria state promoted by the drugs on heme synthesis and destruction. This might be the mechanism underlying the "glucose effect" observed in hepatic porphyrias. The statistical correlation study performed showed association between all the variables studied and reinforce these conclusions.
这项工作研究了模拟急性卟啉症的卟啉原生成药物如何干扰碳水化合物调节激素的状态与关键葡萄糖酶和卟啉症的关系，因为葡萄糖调节疾病的发展。使用不同剂量的 AIA（100、250 和 500mg/kg 体重）和单次剂量的 DDC（50mg DDC/kg 体重），用 2-丙烯基-2-异丙基乙酰胺（AIA）和 3,5-二乙氧基羰基-1,4-二氢吡啶（DDC）处理雌性 Wistar 大鼠。在 AIA/DDC 给药后 16 小时处死大鼠。在接受最高剂量 AIA（H 组）治疗的大鼠中，肝 5-氨基酮戊酸合酶（ALA-S）增加了 300%以上，磷酸烯醇丙酮酸羧激酶（PEPCK）和糖原磷酸化酶（GP）活性分别比对照组低 43%和 46%，血浆胰岛素水平超过正常值 617%，血浆糖皮质激素（GC）下降 20%。GC 结果与肾上腺皮质酮（CORT）产生减少 33%（CORT）和 UDP-葡糖醛酸基转移酶（UGT）代谢减少 62%有关。促肾上腺皮质激素（ACTH）刺激肾上腺产生 3 倍，药物没有改变这一过程。因此，诱导卟啉症的药物 AIA 和 DDC 显著改变了调节碳水化合物代谢的激素状态，增加了胰岛素水平，降低了 GC 的产生、代谢和血浆水平。在这种急性卟啉症模型中，PEPCK 和 GP 抑制活性引起的糖异生和糖原分解阻断主要是由于胰岛素对这些酶的负调节作用。GC 也可能对 PEPCK 阻断有贡献，因为它们受到治疗的抑制，并且是 PEPCK 的正效应物。这些碳水化合物及其调节的紊乱，通过 ALA-S 去阻遏，会增强药物对血红素合成和破坏的促进作用。这可能是肝卟啉症中观察到的“葡萄糖效应”的机制。进行的统计相关性研究表明，所有研究变量之间存在关联，并加强了这些结论。
