Schrenk D, Orzechowski A, Schwarz L R, Snyder R, Burchell B, Ingelman-Sundberg M, Bock K W
Institute of Toxicology, University of Tübingen, Germany.
Environ Health Perspect. 1996 Dec;104 Suppl 6(Suppl 6):1183-8. doi: 10.1289/ehp.961041183.
The hepatic metabolism of benzene is thought to be a prerequisite for its bony marrow toxicity. However, the complete pattern of benzene metabolites formed in the liver and their role in bone marrow toxicity are not fully understood. Therefore, benzene metabolism was studied in isolated rodent hepatocytes. Rat hepatocytes released benzene-1,2-dihydrodiol, hydroquinone (HQ), catechol (CT), phenol (PH), trans-trans-muconic acid, and a number of phase II metabolites such as PH sulfate and PH glucuronide. Pretreatment of animals with 3-methylcholantrene (3-MC) markedly increased PH glucuronide formation while PH sulfate formation was decreased. Likewise, V79 cells transfected with the 3-MC-inducible rat UGT1.6 cDNA showed a considerable rate of PH and HQ glucuronidation. In addition to inducing glucuronidation of phenols, 3-MC treatment (reported to protect rats from the myelotoxicity of benzene) resulted in a decrease of hepatic CYP2E1. In contrast, pretreatment of rats with the CYP2E1-inducer isopropanol strongly enhanced benzene metabolism and the formation of phenolic metabolites. Mouse hepatocytes formed much higher amounts of HQ than rat hepatocytes and considerable amounts of 1,2,4-trihydroxybenzene (THB) sulfate and HQ sulfate. In conclusion, the protective effect of 3-MC in rats is probably due to a shift from the labile PH sulfate to the more stable PH glucuronide, and to a decrease in hepatic CYP2E1. The higher susceptibility of mice toward benzene may be related to the high rate of formation of the myelotoxic metabolite HQ and the semistable phase II metabolites HQ sulfate and THB sulfate.
苯的肝脏代谢被认为是其骨髓毒性的一个先决条件。然而，在肝脏中形成的苯代谢物的完整模式及其在骨髓毒性中的作用尚未完全了解。因此，在分离的啮齿动物肝细胞中研究了苯代谢。大鼠肝细胞释放出苯 - 1,2 - 二醇、对苯二酚（HQ）、儿茶酚（CT）、苯酚（PH）、反 - 反 - 粘康酸，以及一些II相代谢物，如PH硫酸盐和PH葡糖醛酸。用3 - 甲基胆蒽（3 - MC）预处理动物显著增加了PH葡糖醛酸的形成，而PH硫酸盐的形成减少。同样，用3 - MC诱导型大鼠UGT1.6 cDNA转染的V79细胞显示出相当高的PH和HQ葡糖醛酸化速率。除了诱导酚类的葡糖醛酸化外，3 - MC处理（据报道可保护大鼠免受苯的骨髓毒性）导致肝脏CYP2E1减少。相反，用CYP2E1诱导剂异丙醇预处理大鼠强烈增强了苯代谢和酚类代谢物的形成。小鼠肝细胞形成的HQ量比大鼠肝细胞多得多，并且形成了相当数量的1,2,4 - 三羟基苯（THB）硫酸盐和HQ硫酸盐。总之，3 - MC对大鼠的保护作用可能是由于从不稳定的PH硫酸盐向更稳定的PH葡糖醛酸的转变，以及肝脏CYP2E1的减少。小鼠对苯的较高易感性可能与骨髓毒性代谢物HQ以及半稳定的II相代谢物HQ硫酸盐和THB硫酸盐的高形成速率有关。
