Friedberg T, Pritchard M P, Bandera M, Hanlon S P, Yao D, McLaughlin L A, Ding S, Burchell B, Wolf C R
Biomedical Research Centre, University of Dundee, Ninewells Hospital and Medical School, Scotland, UK.
Drug Metab Rev. 1999 May;31(2):523-44. doi: 10.1081/dmr-100101934.
A wide variety of pharmacological and toxicological properties of drugs are determined by cytochrome P450-mediated metabolism. Characterization of these pathways and of the P450 isoenzymes involved constitutes an essential part of drug development. Similarly, because P450s are catalyzing the toxication and detoxication of environmental pollutants, an understanding of these reactions facilitates risk assessment in environmental toxicology. Recently, a variety of recombinant expression systems has been employed to study the role of human P450s in these reactions. These include insect, bacterial, yeast, and mammalian models. As these were developed and characterized by different laboratories, evaluation of their merits and limitations is inherently difficult. To resolve this problem, we have established and characterized the latter three systems and present the key results here. In general, the catalytic properties of P450 isozymes in the various models were rather similar. However, taking technical considerations into account as well as the high level of functional expression of P450s achieved in bacteria make this system ideally suited for drug metabolism research, including the generation of milligram quantities of metabolites for structural determinations. For toxicological studies, however, expression of P450s in mammalian cells was most appropriate. This is exemplified here by studies into the role of human P450s in the activation and inactivation of chemotherapeutic drugs.
药物的多种药理和毒理特性由细胞色素P450介导的代谢作用决定。对这些代谢途径以及相关P450同工酶的特性进行表征是药物研发的重要组成部分。同样，由于P450催化环境污染物的致毒和解毒反应，了解这些反应有助于环境毒理学中的风险评估。最近，多种重组表达系统已被用于研究人类P450在这些反应中的作用。这些系统包括昆虫、细菌、酵母和哺乳动物模型。由于这些系统是由不同实验室开发和表征的，对它们的优缺点进行评估本身就很困难。为了解决这个问题，我们建立并表征了后三种系统，并在此展示关键结果。一般来说，P450同工酶在各种模型中的催化特性相当相似。然而，考虑到技术因素以及在细菌中实现的P450高水平功能表达，使得该系统非常适合药物代谢研究，包括生成毫克级的代谢产物用于结构测定。然而，对于毒理学研究，P450在哺乳动物细胞中的表达最为合适。这里通过研究人类P450在化疗药物的激活和失活中的作用进行了举例说明。
