Toxicity prediction from metabolic pathway modelling

The technique of kinetic simulation, in which a metabolic pathway is modelled by a system of differential equations, has been used to study several questions concerning the teratogenic effects of antifolate drugs. These studies made use of BioCHIMICA, a new biochemical modelling software package. This program is a general-purpose system for simulation of reaction networks. It can simulate systems of over 100 reactions, and can make use of a wide variety of rate equations. Several applications of this program in predicting the teratogenicity of antifolates are described: (a) prediction of relative toxic potency of related analogues, (b) prediction of shapes of dose-response curves in an attempt to determine whether safe exposure levels may exist, (c) prediction of reversibility, i.e. can we distinguish between reversible damage and effects likely to be irreversible, (d) prediction of combined inhibitor effects, i.e. can we identify which teratogenic effects are likely to be synergistic and which antagonistic? These questions were asked in an attempt to predict the toxic effects of a group of experimental inhibitors of thymidylate synthase and dihydrofolate reductase.