Bryant M S, Simmons H F, Harrell R E, Hinson J A
Chemical Industry Institute of Toxicology, Research Triangle Park, NC 27709.
Carcinogenesis. 1994 Oct;15(10):2287-90. doi: 10.1093/carcin/15.10.2287.
Lidocaine (xylocaine) is utilized for the treatment of ventricular arrhythmias which occur during cardiac surgery or myocardial infarction and as a local anesthetic. Recent data from the National Toxicology Program reported that a principal metabolite in man, 2,6-dimethylaniline, is carcinogenic in rats. In addition, the putative metabolite N-hydroxy-2,6-dimethylaniline has been reported to be mutagenic in Salmonella typhimurium TA100. N-Hydroxy metabolites of aromatic amines may be oxidized by hemoglobin to the corresponding nitroso metabolites and the nitroso may covalently bind to cysteine groups in hemoglobin as the corresponding sulfinic acid amide. Since hemoglobin binding is an indirect measure of the formation of the N-hydroxy metabolite, we have examined the possibility that lidocaine or a metabolite may similarly covalently bind to hemoglobin in rats and humans. Using a previously developed gas chromatographic-mas spectrometric assay, hemoglobin adducts of 2,6-dimethylaniline were detected covalently bound to rat hemoglobin after administration of either 2,6-dimethylaniline or lidocaine. Consistent with previously reported observations, low levels of 2,6-dimethylaniline-hemoglobin adducts were also observed in human subjects before lidocaine administration. Following administration of lidocaine, all patients had much higher levels of 2,6-dimethylaniline-hemoglobin adducts. Differences in adduct levels in patients treated with lidocaine (70-3760 mg) ranged from 93 to 636 ng/g hemoglobin. These data indicate that N-hydroxy-2,6-dimethylaniline is a metabolite of lidocaine in man.
利多卡因（赛罗卡因）用于治疗心脏手术或心肌梗死期间发生的室性心律失常，并用作局部麻醉剂。美国国家毒理学计划的最新数据报告称，人体中的一种主要代谢产物2,6 - 二甲基苯胺对大鼠具有致癌性。此外，据报道推定的代谢产物N - 羟基 - 2,6 - 二甲基苯胺在鼠伤寒沙门氏菌TA100中具有致突变性。芳香胺的N - 羟基代谢产物可能被血红蛋白氧化为相应的亚硝基代谢产物，亚硝基可能作为相应的亚磺酸酰胺与血红蛋白中的半胱氨酸基团共价结合。由于血红蛋白结合是N - 羟基代谢产物形成的间接测量方法，我们研究了利多卡因或其代谢产物是否可能同样与大鼠和人类的血红蛋白共价结合的可能性。使用先前开发的气相色谱 - 质谱分析法，在给予2,6 - 二甲基苯胺或利多卡因后，检测到与大鼠血红蛋白共价结合的2,6 - 二甲基苯胺血红蛋白加合物。与先前报道的观察结果一致，在给予利多卡因之前，在人类受试者中也观察到低水平的2,6 - 二甲基苯胺 - 血红蛋白加合物。给予利多卡因后，所有患者的2,6 - 二甲基苯胺 - 血红蛋白加合物水平都高得多。接受利多卡因治疗（70 - 3760 mg）的患者加合物水平差异范围为93至636 ng/g血红蛋白。这些数据表明N - 羟基 - 2,6 - 二甲基苯胺是利多卡因在人体中的一种代谢产物。
