Rolin S, Souhaili-el Amri H, Batt A M, Levy M, Bagrel D, Siest G
Universite Libre de Bruxelles, Département de Biologie Moléculaire, Rhode-St-Genèse, Belgium.
Cell Biol Toxicol. 1989 Jan;5(1):1-14. doi: 10.1007/BF00141060.
The metabolism of albendazole (ABZ), a benzimidazole anthelminthic, was studied in either microsomal preparations of human liver biopsies or cultured human hepatoma cell lines. Metabolites were analyzed by HPLC. Our data show that microsomes from human biopsies and two human cell lines, HepG2 and Hep3B, oxidize the drug to the sulfoxide very efficiently, whereas the third cell line tested, SK-HEP-1, does not. Both cytochrome P-450 dependent monooxygenases and flavin-containing monooxygenases appear to be involved in human ABZ metabolism. Using the cell line displaying the highest ABZ-metabolizing activity, HepG2, the cytotoxic and the inducing effects of the parent drug ABZ and of two primary metabolites, the sulfoxide and the sulfone were studied. These three chemicals provoked a rise in mitotic index resulting from cell division blockage at the prophase or at the metaphase (ABZ metabolites) stage, and ABZ was more cytotoxic than its metabolites. With regard to enzyme-inducing effects, our data clearly demonstrate that the sulfoxide and, to a lesser degree, the sulfone are potent inducers of some drug metabolizing enzymes (i.e., cytochrome P-488 dependent monooxygenases and UDP glucuronyltransferase), whereas ABZ fails to increase and even slightly decreases these enzymatic activities. In conclusion, the HepG2 human hepatoma cell line appears to be suitable for the study of many parameters of metabolism and action of ABZ and other structurally related compounds in humans.
对苯并咪唑驱虫药阿苯达唑（ABZ）的代谢研究是在人肝活检的微粒体制剂或培养的人肝癌细胞系中进行的。代谢产物通过高效液相色谱法进行分析。我们的数据表明，来自人活检组织以及两种人细胞系HepG2和Hep3B的微粒体能够非常有效地将该药物氧化为亚砜，而所测试的第三种细胞系SK-HEP-1则不能。细胞色素P-450依赖性单加氧酶和含黄素单加氧酶似乎都参与了人ABZ的代谢。利用显示出最高ABZ代谢活性的细胞系HepG2，研究了母体药物ABZ以及两种主要代谢产物亚砜和砜的细胞毒性和诱导作用。这三种化学物质导致有丝分裂指数升高，这是由于细胞在前期或中期（ABZ代谢产物）阶段的分裂受阻所致，并且ABZ比其代谢产物的细胞毒性更大。关于酶诱导作用，我们的数据清楚地表明，亚砜以及程度较轻的砜是某些药物代谢酶（即细胞色素P-488依赖性单加氧酶和UDP葡糖醛酸基转移酶）的有效诱导剂，而ABZ未能增加甚至略微降低这些酶活性。总之，HepG2人肝癌细胞系似乎适合用于研究ABZ以及其他结构相关化合物在人体内的许多代谢和作用参数。
