Di Nardo Giovanna, Gilardi Gianfranco
Department of Life Sciences and Systems Biology, University of Torino, via Accademia Albertina 13, 10123 Torino, Italy.
Int J Mol Sci. 2012 Nov 28;13(12):15901-24. doi: 10.3390/ijms131215901.
Drug metabolism in human liver is a process involving many different enzymes. Among them, a number of cytochromes P450 isoforms catalyze the oxidation of most of the drugs commercially available. Each P450 isoform acts on more than one drug, and one drug may be oxidized by more than one enzyme. As a result, multiple products may be obtained from the same drug, and as the metabolites can be biologically active and may cause adverse drug reactions (ADRs), the metabolic profile of a new drug has to be known before this can be commercialized. Therefore, the metabolites of a certain drug must be identified, synthesized and tested for toxicity. Their synthesis must be in sufficient quantities to be used for metabolic tests. This review focuses on the progresses done in the field of the optimization of a bacterial self-sufficient and efficient cytochrome P450, P450 BM3 from Bacillus megaterium, used for the production of metabolites of human enzymes. The progress made in the improvement of its catalytic performance towards drugs, the substitution of the costly NADPH cofactor and its immobilization and scale-up of the process for industrial application are reported.
人类肝脏中的药物代谢是一个涉及多种不同酶的过程。其中，许多细胞色素P450同工酶催化大多数市售药物的氧化反应。每种P450同工酶作用于不止一种药物，且一种药物可能被不止一种酶氧化。因此，同一药物可能会产生多种产物，由于这些代谢产物可能具有生物活性并可能导致药物不良反应（ADR），在新药商业化之前必须了解其代谢概况。因此，必须鉴定、合成并测试某种药物的代谢产物的毒性。其合成量必须足够用于代谢测试。本综述重点关注在优化来自巨大芽孢杆菌的细菌自给自足且高效的细胞色素P450（P450 BM3）方面所取得的进展，该细胞色素P450用于生产人类酶的代谢产物。报道了在提高其对药物的催化性能、替代昂贵的NADPH辅因子以及将其固定化并扩大该过程以用于工业应用方面所取得的进展。
