Designing safer chemicals: Predicting the rates of metabolism of halogenated alkanes
- Univ. of Rochester, NY (United States)
A computational model is presented that can be used as a tool in the design of safer chemicals. This model predicts that rate of hydrogen-atom abstraction by cytochrome P450 enzymes. Excellent correlations between biotransformation rates and the calculated activation energies ({Delta}H{sub act}) of the cytochrome P450-mediated hydrogen-atom abstractions were obtained for the in vitro biotransformation of six halogenated alkanes (1-fluoro-1,1,1,2,2-tetrachloroethane, 1,1,1,2-tetrafluoro-2-chloroethane, 1,1,1,2,2-pentafluoroethane, and 2-bromo-2-chloro-1,1,1-trifluoroethane) with both rat and human enzyme preparations: (rate, human CYP2E1) = 44.99 - 1.79 ({Delta}H{sub act}), r{sup 2} = 0.86; In (rate, human Cyp2E1)= 46399 -1.77 ({Delta}H{sub act}), r{sup 2} = 0.97 (rates are in nmol of product per min per nmol of cytochrome P450 and energies are in kcal/mol). Correlations were also obtained for five inhalation anesthetics (enflurane, sevoflurane, desflurane, methoxyflurane, and isoflurane) for both 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 of safer chemicals, particularly hydrochlorofluorocarbons and inhalation anesthetics. 41 refs., 1 fig., 2 tabs.
- Sponsoring Organization:
- USDOE
- OSTI ID:
- 210131
- Journal Information:
- Proceedings of the National Academy of Sciences of the United States of America, Vol. 92, Issue 24; Other Information: PBD: 21 Nov 1995
- Country of Publication:
- United States
- Language:
- English
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