DESIGNING SAFER CHEMICALS - PREDICTING THE RATES OF METABOLISM OF HALOGENATED ALKANES

A computational model is presented that can be used as a tool in the d esign of safer chemicals, This model predicts the rate of hydrogen-ato m abstraction by cytochrome P450 enzymes, Excellent correlations betwe en biotransformation rates and the calculated activation energies (Del ta H-act) of the cytochrome P450-mediated hydrogen-atom abstractions w ere obtained for the in vitro biotransformation of six halogenated alk anes (1-fluoro-1,1,2,2-tetrachloroethane, dichloroethane,1,1,1,2-tetra fluoro-2-chloroethane, 1,1,1,2,2-pentafluoroethane, and 2-bromo-2-chlo ro-1,1,1-trifluoroethane) with both rat and human enzyme preparations: In(rate, rat liver microsomes) = 44.99 - 1.79(Delta H-act), r(2) = 0. 86; In(rate, human CYP2E1) = 46.99 - 1.77(Delta H-act), r(2) = 0.97 (r ates are in nmol of product per min per nmol of cytochrome P450 and en ergies are in kcal/mol), Correlations were also obtained for five inha lation anesthetics (enflurane, sevoflurane, desflurane, methoxyflurane , and isoflurane) for both in vivo and in vitro metabolism by humans: In[F-](peak plasma) = 42.87 - 1.57(Delta H-act), r(2) = 0.86, To our k nowledge, these are the first in vivo human metabolic rates to he quan titatively predicted, Furthermore, this is one of the first examples,w here computational predictions and in vivo and in vitro data have been shown to agree in any species. The model presented herein provides an archetype for the methodology that may be used in the future design o f safer chemicals, particularly hydrochlorofluorocarbons and inhalatio n anesthetics.