Tsuruda L S, Lamé M W, Jones A D
Department of Molecular Biosciences, University of California-Davis, Davis, CA 95616.
Drug Metab Dispos. 1995 Jan;23(1):129-36.
Naphthalene (NA) is metabolized by pulmonary and hepatic tissues to epoxides, quinones, and their related phase II metabolites. To delineate specific liver metabolites, metabolism was studied in B6C3F1 mouse liver perfused with 5 and 10 mumol/hr [14C]NA. Liver metabolites were compared with urinary metabolites from mice exposed to an equivalent total dose of NA (50 mg/kg ip) to ascertain interorgan and extrahepatic transformation in vivo. Metabolites were separated into pools via hydrophobic columns under neutral (pool I) and acid (pool II) conditions. Pool I contained the majority of [14C] in perfusate and urine. In perfusate, high levels of sulfate conjugates of naphthol and dihydroxynaphthalene were found along with dihydrodiol and glucuronic acid conjugates. In the urine, dihydrodiol was the most abundant metabolite. A novel N-acetylated glutathione conjugate was a constituent of pool II of both perfusate and urine. Additional metabolites identified in urine were N-acetylcysteine conjugate of dihydrodiol epoxide, mercaptolactic acid conjugate of naphthalene oxide (NO), and diglucuronide and sulfate/glucuronide conjugates of dihydroxynaphthalene. Mercapturic acid conjugates of NO were not observed in either perfusate or urine; this finding highlights metabolic differences between strains. Differential covalent binding occurred in cellular fractions, with the highest binding occurring in microsomes and mitochondria. These metabolites indicate that interorgan metabolism plays a role in the disposition of NA in vivo.
萘（NA）在肺和肝组织中代谢生成环氧化物、醌及其相关的II相代谢产物。为了明确肝脏中的特定代谢产物，我们对灌注了5和10 μmol/小时[14C]NA的B6C3F1小鼠肝脏的代谢情况进行了研究。将肝脏代谢产物与暴露于等量总剂量NA（50 mg/kg腹腔注射）的小鼠尿液中的代谢产物进行比较，以确定体内器官间和肝外的转化情况。代谢产物通过疏水柱在中性（组分I）和酸性（组分II）条件下分离成不同组分。组分I在灌注液和尿液中含有大部分的[14C]。在灌注液中，发现了高水平的萘酚和二羟基萘的硫酸盐结合物以及二氢二醇和葡萄糖醛酸结合物。在尿液中，二氢二醇是最丰富的代谢产物。一种新型的N - 乙酰化谷胱甘肽结合物是灌注液和尿液中组分II的成分之一。在尿液中鉴定出的其他代谢产物有二氢二醇环氧化物的N - 乙酰半胱氨酸结合物、萘氧化物（NO）的巯基乳酸结合物以及二羟基萘的双葡萄糖醛酸结合物和硫酸盐/葡萄糖醛酸结合物。在灌注液或尿液中均未观察到NO的巯基尿酸结合物；这一发现突出了不同品系之间的代谢差异。在细胞组分中发生了差异性共价结合，其中微粒体和线粒体中的结合水平最高。这些代谢产物表明器官间代谢在NA在体内的处置过程中发挥了作用。
