Hermanns R C, de Zwart L L, Salemink P J, Commandeur J N, Vermeulen N P, Meerman J H
Leiden/Amsterdam Center for Drug Research, Division of Toxicology, Leiden University, The Netherlands.
Toxicol Sci. 1998 Jun;43(2):241-9. doi: 10.1006/toxs.1998.2429.
There is an increasing need for biomarkers of oxidative stress in animals and man. In this study, we have evaluated in the rat the utility of various endogenous products that are excreted in urine as potential noninvasive biomarkers of oxidative stress in the kidney. Renal oxidative damage was induced by daily i.p. injections of ferric nitrilotriacetate (Fe-NTA) for a period of 13 days. The daily dose of Fe-NTA was increased during the experiment from 6 to 40 mg Fe/kg body wt. The levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), coproporphyrin III (COPRO III), seven aldehydes, and acetone were determined in fractionated urine samples and compared with commonly used urinary and plasma clinical chemical parameters for toxicity. The parameters that showed the earliest increase were acetaldehyde (ACET), propanal (PROPA), and COPRO III. Their increase was significantly earlier than that of classical clinical chemical parameters indicative of renal damage such as urinary concentration of glucose (GLU) and protein (PRT), and N-acetyl-beta-D-glucosaminidase (NAG) activity. The excretion of 8-OHdG was increased only after administration of the highest dose of Fe-NTA. Urinary excretion of acetone, form-aldehyde (FOR), butanal (BUTA), pentanal (PENTA) hexanal (HEXA), and malondialdehyde (MDA) was also increased; however, their increase occurred only slightly before or simultaneously with that of the urinary clinical chemical parameters. In conclusion, 8-OHdG, acetone, FOR, BUTA, PENTA, HEXA, and MDA may possibly serve as biomarkers for oxidative kidney damage. COPRO III, ACET, and PROPA might even be used as biomarkers of production of reactive oxygen species at an early stage.
动物和人类对氧化应激生物标志物的需求日益增加。在本研究中，我们评估了大鼠尿液中排泄的各种内源性产物作为肾脏氧化应激潜在非侵入性生物标志物的效用。通过每天腹腔注射次氮基三乙酸铁（Fe-NTA）持续13天诱导肾脏氧化损伤。实验期间Fe-NTA的每日剂量从6毫克铁/千克体重增加到40毫克铁/千克体重。在分级尿液样本中测定8-羟基-2'-脱氧鸟苷（8-OHdG）、粪卟啉III（COPRO III）、七种醛和丙酮的水平，并与常用的尿液和血浆临床化学毒性参数进行比较。最早升高的参数是乙醛（ACET）、丙醛（PROPA）和COPRO III。它们的升高明显早于指示肾脏损伤的经典临床化学参数，如尿液中葡萄糖（GLU）和蛋白质（PRT）的浓度以及N-乙酰-β-D-氨基葡萄糖苷酶（NAG）活性。仅在给予最高剂量的Fe-NTA后8-OHdG的排泄才增加。丙酮、甲醛（FOR）、丁醛（BUTA）、戊醛（PENTA）、己醛（HEXA）和丙二醛（MDA）的尿液排泄也增加；然而，它们的增加仅略早于或与尿液临床化学参数的增加同时发生。总之，8-OHdG、丙酮、FOR、BUTA、PENTA、HEXA和MDA可能作为肾脏氧化损伤的生物标志物。COPRO III、ACET和PROPA甚至可能用作早期活性氧产生的生物标志物。
