PROXIMAL: a method for Prediction of Xenobiotic Metabolism

Abstract

Background: Contamination of the environment with bioactive chemicals has emerged as a potential public health risk. These substances that may cause distress or disease in humans can be found in air, water and food supplies. An open question is whether these chemicals transform into potentially more active or toxic derivatives via xenobiotic metabolizing enzymes expressed in the body. We present a new prediction tool, which we call PROXIMAL (Prediction of Xenobiotic Metabolism) for identifying possible transformation products of xenobiotic chemicals in the liver. Using reaction data from DrugBank and KEGG, PROXIMAL builds look-up tables that catalog the sites and types of structural modifications performed by Phase I and Phase II enzymes. Given a compound of interest, PROXIMAL searches for substructures that match the sites cataloged in the look-up tables, applies the corresponding modifications to generate a panel of possible transformation products, and ranks the products based on the activity and abundance of the enzymes involved.

Results: PROXIMAL generates transformations that are specific for the chemical of interest by analyzing the chemical's substructures. We evaluate the accuracy of PROXIMAL's predictions through case studies on two environmental chemicals with suspected endocrine disrupting activity, bisphenol A (BPA) and 4-chlorobiphenyl (PCB3). Comparisons with published reports confirm 5 out of 7 and 17 out of 26 of the predicted derivatives for BPA and PCB3, respectively. We also compare biotransformation predictions generated by PROXIMAL with those generated by METEOR and Metaprint2D-react, two other prediction tools.

Conclusions: PROXIMAL can predict transformations of chemicals that contain substructures recognizable by human liver enzymes. It also has the ability to rank the predicted metabolites based on the activity and abundance of enzymes involved in xenobiotic transformation.

Fig. 1

Schematic illustration of look-up table construction (PROXIMAL step 1). a A CYP reaction transforms the drug antipyrine to 3-hydroxymethylantipyrine, both represented in KEGG atom type format. Red, blue and green atoms are the reaction centers, adjacent neighbors and distant neighbors, respectively. The .mol files were downloaded from DrugBank. b List of matched atoms for the reactant and product. c The transformation look-up table has two parts, consisting of a key that specifies the modified reactant substructure and a corresponding value that describes the modifications resulting in the product

Fig. 2

Schematic illustration of generating the transformation products (PROXIMAL step 2). a The example drug, acetaminophen, is shown represented in KEGG atom type format. The .mol file was downloaded from KEGG. b A list of atoms comprising acetaminophen and their adjacent and distant neighbors. c The products predicted to result from modifications of the reaction center at atom number 11 are N-acetyl-p-benzoquinone imine, acetaminophen glucuronide and acetaminophen sulfate

Fig. 3

a Representation of BPA in KEGG atom type format. Each atom is represented by a number, which corresponds to the atom order in the .mol file (downloaded from KEGG), and its KEGG atom type. b Unique BPA atoms and their adjacent and distant neighbors are listed. Each atom of BPA is considered a reaction center, which can have up to four adjacent neighbors

Fig. 4

Predicted biotransformation products for BPA. The solid and dashed lines represent biotransformation through Phase I and Phase II, respectively. The symbol † indicates that the exact predicted compound has been verified by experimental data, whereas the symbol * indicates the predicted compound is similar to but not exactly the same as the structure reported in literature. The numeric subscripts identify the metabolites in the text

Fig. 5

PCB3 representation in KEGG atom type format. Each atom is represented by a number, which corresponds to the atom order in the .mol file (from KEGG), and its KEGG atom type

Fig. 6

Predicted biotransformation products for PCB3. The solid and dashed lines represent the biotransformation reactions mediated by Phase I and Phase II enzymes, respectively. The symbol † indicates that the exact compound has been experimentally observed