Schrenk D, Ingelman-Sundberg M, Bock K W
Institute of Toxicology, University of Tübingen, FRG.
Drug Metab Dispos. 1992 Mar-Apr;20(2):137-41.
The influence of P-4502E1 induction on the metabolite pattern of benzene was studied in hepatocytes in vitro and in bile in vivo, and compared with that obtained with phenol (the major benzene metabolite). Eight metabolites from benzene and four from phenol (including conjugates) represented over 90% of total metabolites. Benzene metabolism (0.1 mM) in hepatocytes from isopropanol-treated rats (2.5 ml/kg, orally) was 3-fold higher than in corresponding cells from control rats, primarily because of increased formation of hydroquinone and phenylglutathione. Immunoblotting of microsomes revealed a parallel induction of P-4502E1 in hepatocytes from isopropanol-treated rats. In contrast, treatment with 3-methylcholanthrene or phenobarbital caused a decrease of P-4502E1, together with reduced benzene metabolism at 0.01 mM benzene. Addition of isoniazid (5 mM) resulted in a strong inhibition of benzene and phenol metabolism. Benzene metabolites were determined in bile following intraperitoneal administration of benzene (2.5 and 150 mg/kg). Biliary benzene metabolites were increased 2- to 3-fold after isopropanol treatment. Hydroquinone sulfate was identified as a major biliary metabolite of phenol. The results suggest that treatment with inducers of P-4502E1 leads, even at low benzene exposure, to an increased release of potentially myelotoxic metabolites from liver into the systemic circulation.
在体外肝细胞和体内胆汁中研究了P-4502E1诱导对苯代谢产物模式的影响，并与苯酚（主要的苯代谢产物）的情况进行了比较。苯的8种代谢产物和苯酚的4种代谢产物（包括结合物）占总代谢产物的90%以上。异丙醇处理的大鼠（2.5 ml/kg，口服）肝细胞中的苯代谢（0.1 mM）比对照大鼠相应细胞中的高3倍，主要是因为对苯二酚和苯巯基尿酸的生成增加。微粒体的免疫印迹显示异丙醇处理的大鼠肝细胞中P-4502E1有平行诱导。相反，用3-甲基胆蒽或苯巴比妥处理会导致P-4502E1减少，同时在0.01 mM苯时苯代谢降低。加入异烟肼（5 mM）会强烈抑制苯和苯酚的代谢。腹腔注射苯（2.5和150 mg/kg）后测定胆汁中的苯代谢产物。异丙醇处理后胆汁中的苯代谢产物增加了2至3倍。硫酸对苯二酚被鉴定为苯酚的主要胆汁代谢产物。结果表明，即使在低苯暴露情况下，用P-4502E1诱导剂处理也会导致肝脏中潜在的骨髓毒性代谢产物向体循环的释放增加。
