Mendrala A L, Langvardt P W, Nitschke K D, Quast J F, Nolan R J
Toxicology Research Laboratory, Dow Chemical Company, Midland, MI 48674.
Arch Toxicol. 1993;67(1):18-27. doi: 10.1007/BF02072030.
Styrene oxide (SO), a labile metabolite of styrene, is generally accepted as being responsible for any genotoxicity associated with styrene. To better define the hazard associated with styrene, the activity of the enzymes involved in the formation (monooxygenase) and destruction of SO (epoxide hydrolase and glutathione-S-transferase) were measured in the liver and lungs from naive and styrene-exposed male Sprague-Dawley rats and B6C3F1 mice (three daily 6-h inhalation exposures at up to 600 ppm styrene) and Fischer 344 rats (four daily 6-h inhalation exposures at up to 1000 ppm styrene), and in samples of human liver tissue. Additionally, the time course of styrene and SO in the blood was measured following oral administration of 500 mg styrene/kg body weight to naive Fischer rats and rats previously exposed to 1000 ppm styrene. The affinity of hepatic monooxygenase for styrene, as measured by the Michaelis constant (Km), was similar in the rat, mouse, and human. Based on the Vmax for monooxygenase activity and the relative liver and body size, the mouse had the greatest capacity and humans the lowest capacity to form SO from styrene. In contrast, human epoxide hydrolase and a greater affinity (i.e., lower Km) for SO than epoxide hydrolase from rats or mice while the apparent Vmax for epoxide hydrolase was similar in the rat, mouse, and human liver. However, the activity of epoxide hydrolase relative to monooxygenase activity was much greater in the human than in the rodent liver. Hepatic glutathione-S-transferase activity, as indicated by the Vmax, was 6- to 33-fold higher than epoxide hydrolase activity. However, the significance of the high glutathione-S-transferase activity is unknown because hydrolysis, rather than conjugation, is the primary pathway for SO detoxification in vivo. Human hepatic glutathione-S-transferase activity was extremely variable between individual human livers and much lower than in rat or mouse liver. Prior exposure to styrene had no effect on monooxygenase activity or on blood styrene levels in rats given a large oral dose of styrene. In contrast, prior exposure to styrene increased hepatic epoxide hydrolase activity 1.6-fold and resulted in lower (0.1 > P > 0.05) blood SO levels in rats given a large oral dose of styrene. Qualitatively, these data indicate that the mouse has the greatest capacity and the human the lowest capacity to form SO. In addition, human liver should be more effective than rodent liver in hydrolyzing low levels of SO.(ABSTRACT TRUNCATED AT 400 WORDS)
氧化苯乙烯（SO）是苯乙烯的一种不稳定代谢产物，通常被认为是与苯乙烯相关的任何遗传毒性的起因。为了更好地界定与苯乙烯相关的危害，我们测定了未接触过苯乙烯和接触过苯乙烯的雄性斯普拉格-道利大鼠、B6C3F1小鼠（每天6小时吸入高达600 ppm苯乙烯，共3天）以及费希尔344大鼠（每天6小时吸入高达1000 ppm苯乙烯，共4天）的肝脏和肺中参与SO形成（单加氧酶）和分解（环氧化物水解酶和谷胱甘肽-S-转移酶）的酶的活性，以及人体肝脏组织样本中的酶活性。此外，在给未接触过苯乙烯的费希尔大鼠和先前接触过1000 ppm苯乙烯的大鼠口服500 mg苯乙烯/千克体重后，测定了血液中苯乙烯和SO的时间进程。通过米氏常数（Km）测量的肝脏单加氧酶对苯乙烯的亲和力，在大鼠、小鼠和人类中相似。基于单加氧酶活性的最大反应速度（Vmax）以及相对肝脏和身体大小，小鼠从苯乙烯形成SO的能力最强，而人类的能力最低。相比之下，人类环氧化物水解酶对SO的亲和力更高（即Km更低），高于大鼠或小鼠的环氧化物水解酶，而环氧化物水解酶的表观Vmax在大鼠、小鼠和人类肝脏中相似。然而，人类肝脏中环氧化物水解酶相对于单加氧酶活性的活性比啮齿动物肝脏中的大得多。以Vmax表示的肝脏谷胱甘肽-S-转移酶活性比环氧化物水解酶活性高6至33倍。然而，谷胱甘肽-S-转移酶活性高的意义尚不清楚，因为水解而非结合是体内SO解毒的主要途径。人体肝脏中的谷胱甘肽-S-转移酶活性在个体之间差异极大，且远低于大鼠或小鼠肝脏中的活性。预先接触苯乙烯对给予大剂量口服苯乙烯的大鼠的单加氧酶活性或血液苯乙烯水平没有影响。相比之下，预先接触苯乙烯使给予大剂量口服苯乙烯的大鼠的肝脏环氧化物水解酶活性增加了1.6倍，并导致血液中SO水平降低（0.1＞P＞0.05）。定性地说，这些数据表明小鼠形成SO的能力最强，而人类的能力最低。此外，人体肝脏在水解低水平SO方面应比啮齿动物肝脏更有效。（摘要截断于400字）
