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PULMONARY BIOACTIVATION OF TRICHLOROETHYLENE TO CHLORAL HYDRATE: RELATIVE CONTRIBUTIONS OF CYP2E1, CYP2F, AND CYP2B1

Department of Anatomy and Cell Biology, Queen's University, Kingston, Ontario, Canada (P.G.F., B.M., K.S.C.); Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California (R.M.B., M.A.S.); and Department of Pharmacology, Wayne State University School of Medicine, Detroit, Michigan (L.H.L., D.A.P.)

Pulmonary cytotoxicity induced by trichloroethylene (TCE) is associated with cytochrome P450-dependent bioactivation to reactive metabolites. In this investigation, studies were undertaken to test the hypothesis that TCE metabolism to chloral hydrate (CH) is mediated by cytochrome P450 enzymes, including CYP2E1, CYP2F, and CYP2B1. Recombinant rat CYP2E1 catalyzed TCE metabolism to CH with greater affinity than did the recombinant P450 enzymes, rat CYP2F4, mouse CYP2F2, rat CYP2B1, and human CYP2E1. The catalytic efficiencies of recombinant rat CYP2E1 (V_max/K_m = 0.79) for generating CH was greater than those of recombinant CYP2F4 (V_max/K_m = 0.27), recombinant mouse CYP2F2 (V_max/K_m = 0.11), recombinant rat CYP2B1 (V_max/K_m = 0.07), or recombinant human CYP2E1 (V_max/K_m = 0.02). Decreases in lung microsomal immunoreactive CYP2E1, CYP2F2, and CYP2B1 were manifested at varying time points after TCE treatment. The loss of immunoreactive CYP2F2 occurred before the loss of immunoreactive CYP2E1 and CYP2B1. These protein decreases coincided with marked reduction of lung microsomal p-nitrophenol hydroxylation and pentoxyresorufin O-dealkylation. Rates of CH formation in the microsomal incubations were time-dependent and were incremental from 5 to 45 min. The production of CH was also determined in human lung microsomal incubations. The rates were low and were detected in only three of eight subjects. These results showed that, although CYP2E1, CYP2F, and CYP2B1 are all capable of generating CH, TCE metabolism is mediated with greater affinity by recombinant rat CYP2E1 than by recombinant CYP2F, CYP2B1, or human CYP2E1. Moreover, the rates of CH production were substantially higher in murine than in human lung.

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