Metabolism of the tropine indole-3-carboxylate ICS 205-930 by differentiated rat and human hepatoma cells.

Molecular toxicology Pub Date : 1987-09-01
V Fischer, J P Baldeck, F J Wiebel
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Abstract

The metabolism of the tropine indole-3-carboxylate ICS 205-930 (ICS), a highly potent and selective antagonist of 5-HT3 receptors, was investigated in continuous cell lines derived from rat or human liver and compared to the in vivo metabolism in rat and human. The well-differentiated rat hepatoma line 2sFou extensively metabolized ICS by hydroxylation of the indole moiety and subsequent conjugation to form the corresponding glucuronides and sulfates. The 2sFou cells also oxidized ICS at the tropinyl moiety to form both N-demethyl and N-oxide derivatives. The relative amount of the various metabolites was dependent on the substrate concentration. Pretreatment of the cells with dexamethasone increased the rate of metabolism for all pathways, while benz[a]anthracene caused an increase in hydroxylation at the indole moiety at the expense of N-oxidation. Phenobarbital pretreatment had no effect on ICS metabolism. The pattern of metabolites formed in 2sFou cells was qualitatively similar to that formed in rat urine. The human hepatoma line HepG2 metabolized ICS only to a small extent. The HepG2 cells failed to form detectable amounts of ICS conjugates found in human urine. The N-oxide-ICS was not found in HepG2 cells or in human urine. Virtually no ICS metabolites were found in human lung adenocarcinoma lines NCI-H358 or NCI-H322. The results suggest that continuous cell lines such as the differentiated rat hepatoma cells 2sFou might be used to mimic the metabolism of xenobiotics in rat and to clarify their complex metabolic pathways.

托品吲哚-3-羧酸酯ICS 205-930在分化的大鼠和人肝癌细胞中的代谢。
研究了5-HT3受体高效选择性拮抗剂托品吲哚-3-羧酸酯ICS 205-930 (ICS)在大鼠和人肝脏连续细胞系中的代谢,并与大鼠和人体内代谢进行了比较。分化良好的大鼠肝癌细胞系2sfu通过吲哚部分的羟基化和随后的偶联形成相应的葡萄糖醛酸盐和硫酸盐,广泛代谢ICS。2sfo细胞还氧化了ICS的tropinyl部分,形成n -去甲基和n -氧化物衍生物。各种代谢物的相对量取决于底物浓度。用地塞米松预处理细胞增加了所有途径的代谢速率,而苯[a]蒽引起吲哚部分羟基化的增加,以牺牲n氧化为代价。苯巴比妥预处理对ICS代谢无影响。在2sfu细胞中形成的代谢物的模式与在大鼠尿液中形成的模式在质量上相似。人肝癌细胞系HepG2仅在很小程度上代谢ICS。HepG2细胞不能形成在人尿中发现的可检测量的ICS偶联物。在HepG2细胞和人尿中均未发现n -氧化物ics。在人肺腺癌细胞系NCI-H358或NCI-H322中几乎没有发现ICS代谢物。结果表明,连续细胞系如分化的大鼠肝癌细胞2sfu可用于模拟大鼠体内的外源药物代谢,并阐明其复杂的代谢途径。
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