Sprague Christopher L, Elfarra Adnan A
School of Veterinary Medicine, 2015 Linden Drive, Madison, WI 53706, USA.
Drug Metab Dispos. 2003 Aug;31(8):986-92. doi: 10.1124/dmd.31.8.986.
Epidemiological studies have indicated that 1,3-butadiene exposure is associated with an increased risk of leukemia. In human liver microsomes, 1,3-butadiene is rapidly oxidized to butadiene monoxide, which can then be hydrolyzed to 3-butene-1,2-diol (BDD). In this study, BDD and several potential metabolites were characterized in the urine of male B6C3F1 mice and Sprague-Dawley rats after BDD administration (i.p.). Rats given 1420 micromol kg(-1) BDD excreted significantly greater amounts of BDD relative to rats administered 710 micromol kg(-1) BDD. Rats administered 1420 or 2840 micromol kg(-1) BDD excreted significantly greater amounts of BDD per kilogram of body weight than mice given an equivalent dose. Trace amounts of 1-hydroxy-2-butanone and the carboxylic acid metabolites, crotonic acid, propionic acid, and 2-ketobutyric acid, were detected in mouse and rat urine after BDD administration. Because of the identification of the carboxylic acid metabolites and because of the known ability of carboxylic acids to conjugate coenzyme A, which is critical for hippuric acid formation, the effect of BDD treatment on hippuric acid concentrations was investigated. Rats given 1420 or 2272 micromol kg(-1) BDD had significantly elevated ratios of benzoic acid to hippuric acid in the urine after treatment compared with control urine. However, this effect was not observed in mice administered 1420 or 2840 micromol kg(-1) BDD. Collectively, the results demonstrate species differences in the urinary excretion of BDD and show that BDD administration in rats inhibits hippuric acid formation. The detection of 1-hydroxy-2-butanone and the carboxylic acids also provides insight regarding pathways of BDD metabolism in vivo.
流行病学研究表明，接触1,3 - 丁二烯会增加患白血病的风险。在人肝微粒体中，1,3 - 丁二烯会迅速氧化为丁二烯 monoxide，然后可水解为3 - 丁烯 - 1,2 - 二醇（BDD）。在本研究中，对雄性B6C3F1小鼠和Sprague - Dawley大鼠经腹腔注射BDD后尿液中的BDD及几种潜在代谢物进行了表征。给予1420微摩尔/千克BDD的大鼠相对于给予710微摩尔/千克BDD的大鼠排泄出的BDD量显著更多。给予1420或2840微摩尔/千克BDD的大鼠每千克体重排泄的BDD量比给予同等剂量的小鼠显著更多。BDD给药后，在小鼠和大鼠尿液中检测到痕量的1 - 羟基 - 2 - 丁酮以及羧酸代谢物巴豆酸、丙酸和2 - 酮丁酸。由于鉴定出了羧酸代谢物，且已知羧酸具有结合辅酶A的能力，而辅酶A对马尿酸形成至关重要，因此研究了BDD处理对马尿酸浓度的影响。与对照尿液相比，给予1420或2272微摩尔/千克BDD的大鼠在处理后尿液中苯甲酸与马尿酸的比值显著升高。然而，在给予1420或2840微摩尔/千克BDD的小鼠中未观察到这种效应。总体而言，结果表明BDD的尿排泄存在物种差异，并表明在大鼠中给予BDD会抑制马尿酸的形成。1 - 羟基 - 2 - 丁酮和羧酸的检测也为BDD在体内的代谢途径提供了见解。
