de Zwart L L, Hermanns R C, Meerman J H, Commandeur J N, Salemink P J, Vermeulen N P
Leiden-Amsterdam Center for Drug Research (LACDR), Department of Pharmacochemistry, Vrije Universiteit, Amsterdam, The Netherlands.
Toxicol Appl Pharmacol. 1998 Jan;148(1):71-82. doi: 10.1006/taap.1997.8310.
Carbon tetrachloride (CCl4) is a model compound for inducing free radical damage in liver. In this study 10 biomarkers in rats treated i.p. with three different single doses of CCl4 (0.25, 0.50, and 1.00 ml/kg body wt) were measured dose and time dependently and compared to evaluate these urinary products as noninvasive biomarkers for radical damage. Eight degradation products of lipid peroxides, namely, formaldehyde, acetaldehyde, acetone, propanal, butanal, pentanal, hexanal, and malondialdehyde (MDA), 8-hydroxy-2'-deoxyguanosine (8-OH-dG) and coproporphyrin III were measured in this study. As general measures of toxicity, several clinical chemical parameters (n = 12) and histopathological damage were determined. A dose-dependent increase in both the clinical parameters and the lipid degradation products was found. Increases in lipid degradation products were statistically significant at doses of 0.5 and 1 ml/kg CCl4. An increase in these products was already found in the first 12 h after exposure. At the lowest dose, 0.25 ml/kg CCl4, acetaldehyde and propanal already showed a statistically significant increase as well. No change in the urinary levels of 8-OH-dG could be found in this study and a decrease in the urinary excretion of coproporphyrin III was found. It is concluded that 8-OH-dG and coproporphyrin III are not useful biomarkers for radical damage induced by CCl4. Lipid degradation products, however, are promising noninvasive biomarkers for in vivo radical damage, although the precise specificity of these biomarkers for damage induced by radicals needs to be further investigated.
四氯化碳（CCl4）是用于诱导肝脏自由基损伤的模型化合物。在本研究中，对腹腔注射三种不同单剂量CCl4（0.25、0.50和1.00 ml/kg体重）的大鼠体内10种生物标志物进行了剂量和时间依赖性测量，并进行比较，以评估这些尿液产物作为自由基损伤的非侵入性生物标志物。本研究测定了脂质过氧化物的8种降解产物，即甲醛、乙醛、丙酮、丙醛、丁醛、戊醛、己醛和丙二醛（MDA）、8-羟基-2'-脱氧鸟苷（8-OH-dG）和粪卟啉III。作为毒性的一般指标，测定了几个临床化学参数（n = 12）和组织病理学损伤。发现临床参数和脂质降解产物均呈剂量依赖性增加。在CCl4剂量为0.5和1 ml/kg时，脂质降解产物的增加具有统计学意义。在接触后的前12小时内就已发现这些产物增加。在最低剂量0.25 ml/kg CCl4时，乙醛和丙醛也已显示出统计学意义的增加。本研究未发现8-OH-dG尿液水平有变化，且发现粪卟啉III的尿排泄减少。结论是，8-OH-dG和粪卟啉III不是CCl4诱导的自由基损伤的有用生物标志物。然而，脂质降解产物是有前景的体内自由基损伤非侵入性生物标志物，尽管这些生物标志物对自由基诱导损伤的确切特异性需要进一步研究。
