Modelling the metabolic action of human and rat CYP1A2 and its relationship with the carcinogenicity of heterocyclic amines

• Type: Article in International Scientific Journal
• Date: 2003

Authors

Da Fonseca, R (Author) Other; Menziani, MC (Author) Other; Melo, A (Author) FCUP; Ramos, MJ (Author) FCUP

Journal

Title: Molecular Physics

Vol. 101

Pages: 2731-2741

ISSN: 0026-8976

Publisher: Taylor & Francis

Indexing

ISI Web of Knowledge - 4 Citations

Scopus - 5 Citations

Scientific classification

FOS: Natural sciences > Physical sciences

Other information

Authenticus ID: P-000-F5Y

DOI: 10.1080/00268970310001603112

Abstract (EN): Cytochrome P450 (CYP) is a family of enzymes responsible for organism detoxification. However, some of the members of the CYP1A subfamily also catalyse the activation of heterocyclic amines (HAs), present in cooked meat, to carcinogenic compounds which have been shown to increase the risk of breast, colorectal and lung cancer. In humans, CYP1A2 is the enzyme with the most significant action in HA metabolism but in rodents CYP1A1 is also important in this biotransformation. Understanding the metabolic action of these enzymes is essential to predict the factors that enable the formation of the carcinogenic products. We have built two models of CYP1A2, one for the human enzyme and one for the rat homologue. The templates chosen include the only X-ray structure published to date for a mammal CYP, a quimeric C2A5 from rabbit, as well as CYPs belonging to Bacillus megaterium (CYPBm-3), Pseudomonas putida (CYPcam), Pseudomonas sp. (CYPterp), and Saccharopolyspora erythraea (CYPeryf). Two HAs, MeIQ (2-amino-3,4-dimethylimidazo[4,5-f] quinoline) and MeIQx (2-amino-3,8-dimethylimidazo[4,5-f] quinoxaline), known substrates of human and rat CYPIA2, were docked in the active site of the models, providing information regarding the different catalytic rates associated with the metabolisms in both enzymes. This is important for analysing the behaviour of animal models concerning the testing of anticancer drugs.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 11