Boogaard P J, Bond J A
Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709-2137, USA.
Toxicol Appl Pharmacol. 1996 Dec;141(2):617-27. doi: 10.1006/taap.1996.0328.
1,2:3,4-Diepoxybutane (BDE) is probably the ultimate genotoxic metabolite of the rodent carcinogen 1,3-butadiene (BD). The formation of BDE from BD has been characterized in vitro using tissues from rats, mice, and humans. For assessment of human risk following exposure to BD, a quantitative understanding between the balance of formation and inactivation of BDE is essential. BDE can be removed by glutathione (GSH) conjugation and by hydrolysis. Recently, significant species differences were reported in GSH conjugation of BDE in vitro, with rats being more efficient than humans and mice being much more efficient than either rats or humans (Boogaard et al., Toxicol. Appl. Pharmacol. 136, 307, 1996). In the present study the microsomal hydrolysis of BDE was quantified using tissues of rats, mice, and humans. Hydrolysis of BDE was well described by Michaelis-Menten kinetics. Two metabolites, erythritol and anhydroerythritol, were identified following incubation of BDE with human microsomes, but these metabolites did not fully account for the disappearance of BDE, suggesting that there may be other as yet unidentified routes of metabolism. In contrast to GSH conjugation, which was most efficient in mice compared with rats or humans, the efficiency of hydrolysis as expressed by Vmax/Km was much lower in mouse (3.93 microl/min/mg protein) than in rat (19.2) or human (32.5) liver. Pulmonary hydrolysis was also most efficient in humans, with average Vmax/Km values of 7.7, 6.7, and 2.7 microl/min/mg protein for humans, mice, and rats, respectively. However, the interindividual variation among the human samples was considerable with individual Vmax/Km values varying from 17.9 to 49.5 microl/min/mg protein for liver and from 4.57 to 16.2 microl/min/mg protein for lung tissue. This means that the heterogeneity among humans in the formation as well as in the removal of BDE will be an important factor in human risk assessment. The present data, coupled with earlier studies on formation and removal of BDE and the observation that GSH conjugation of BDE is a potentially mutagenic pathway, explain the high susceptibility of mice to BD-induced carcinogenesis.
1,2:3,4-二环氧丁烷（BDE）可能是啮齿动物致癌物1,3-丁二烯（BD）的最终遗传毒性代谢产物。已利用大鼠、小鼠和人类的组织在体外对BD形成BDE的过程进行了表征。为评估人类接触BD后的风险，定量了解BDE形成与失活之间的平衡至关重要。BDE可通过谷胱甘肽（GSH）结合和水解作用被清除。最近有报道称，体外BDE的GSH结合存在显著的物种差异，大鼠比人类更有效，而小鼠比大鼠或人类都更有效（Boogaard等人，《毒理学与应用药理学》136卷，307页，1996年）。在本研究中，使用大鼠、小鼠和人类的组织对BDE的微粒体水解进行了定量。BDE的水解可用米氏动力学很好地描述。将BDE与人微粒体孵育后，鉴定出了两种代谢产物，即赤藓醇和脱水赤藓醇，但这些代谢产物并不能完全解释BDE的消失，这表明可能存在其他尚未确定的代谢途径。与GSH结合（在小鼠中比大鼠或人类更有效）相反，以Vmax/Km表示的水解效率在小鼠肝脏中（3.93微升/分钟/毫克蛋白质）比在大鼠（19.2）或人类（32.5）肝脏中要低得多。肺部水解在人类中也最有效，人类、小鼠和大鼠的平均Vmax/Km值分别为7.7、6.7和2.7微升/分钟/毫克蛋白质。然而，人类样本之间的个体差异相当大，肝脏的个体Vmax/Km值在17.9至49.5微升/分钟/毫克蛋白质之间，肺组织的个体Vmax/Km值在4.57至16.2微升/分钟/毫克蛋白质之间。这意味着人类在BDE形成以及清除方面的异质性将是人类风险评估中的一个重要因素。目前的数据，加上早期关于BDE形成和清除的研究以及观察到BDE的GSH结合是一条潜在的诱变途径，解释了小鼠对BD诱导的致癌作用的高度易感性。
