利用人肝微粒体和人淋巴细胞评估苯并[a]芘、黄曲霉毒素B1、萘和他莫昔芬的遗传毒性和细胞毒性代谢产物的生成情况。

Evaluation of the generation of genotoxic and cytotoxic metabolites of benzo[a]pyrene, aflatoxin B1, naphthalene and tamoxifen using human liver microsomes and human lymphocytes.

Wilson A S, Tingle M D, Kelly M D, Park B K

Department of Pharmacology and Therapeutics, University of Liverpool, UK.

Hum Exp Toxicol. 1995 Jun;14(6):507-15. doi: 10.1177/096032719501400608.

Abstract

The ability of model stable epoxides and metabolites generated by human liver microsomes from benzo[a]pyrene, aflatoxin B1, naphthalene and tamoxifen to produce cytotoxicity and genotoxicity in human peripheral lymphocytes has been investigated. 2. The stable epoxides 1,1,1 trichloropropene-2,3-oxide (100 microM) and trans stilbene oxide (100 microM) as well as metabolites generated from aflatoxin B1 (30 microM) and naphthalene (100 microM) by an extracellular metabolising system were toxic to isolated resting mononuclear leucocytes (MNLs), whereas glycidol (100 microM), benzo[a]pyrene (100 microM) and tamoxifen (50 microM) were not. 3. The stable epoxides 1,1,1 trichloropropene-2,3-oxide (100 microM) and trans stilbene oxide (100 microM) but not glycidol (100 microM) were toxic to dividing lymphocytes only after a 72-h exposure. Tamoxifen (30 microM), aflatoxin B1 (30 microM) and their metabolites were also toxic to dividing lymphocytes. Benzo[a]pyrene (100 microM) and naphthalene (100 microM) were not toxic either in the absence or presence of the extracellular metabolising system. 4. Benzo[a]pyrene (100 microM) and aflatoxin B1 (30 microM) were directly genotoxic to lymphocytes, this genotoxicity was significantly enhanced by the presence of the extracellular metabolising system. This indicates that both intracellular and extracellular bioactivation of these two compounds can produce genotoxicity. In contrast, naphthalene and tamoxifen were non-genotoxic.

摘要

已对人肝微粒体由苯并[a]芘、黄曲霉毒素B1、萘和他莫昔芬生成的模型稳定环氧化物和代谢产物在人外周淋巴细胞中产生细胞毒性和遗传毒性的能力进行了研究。2. 稳定环氧化物1,1,1-三氯丙烯-2,3-氧化物（100微摩尔）和反式芪氧化物（100微摩尔）以及由细胞外代谢系统从黄曲霉毒素B1（30微摩尔）和萘（100微摩尔）生成的代谢产物对分离的静息单核白细胞（MNLs）有毒性，而缩水甘油（100微摩尔）、苯并[a]芘（100微摩尔）和他莫昔芬（50微摩尔）则无毒性。3. 稳定环氧化物1,1,1-三氯丙烯-2,3-氧化物（100微摩尔）和反式芪氧化物（100微摩尔），但缩水甘油（100微摩尔）仅在72小时暴露后对分裂淋巴细胞有毒性。他莫昔芬（30微摩尔）、黄曲霉毒素B1（30微摩尔）及其代谢产物对分裂淋巴细胞也有毒性。苯并[a]芘（100微摩尔）和萘（100微摩尔）在有无细胞外代谢系统的情况下均无毒性。4. 苯并[a]芘（100微摩尔）和黄曲霉毒素B1（30微摩尔）对淋巴细胞有直接遗传毒性，细胞外代谢系统的存在显著增强了这种遗传毒性。这表明这两种化合物的细胞内和细胞外生物活化均可产生遗传毒性。相比之下，萘和他莫昔芬无遗传毒性。