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First published on June 29, 2005; DOI: 10.1124/dmd.105.005074

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Received for publication April 12, 2005.
Revised June 21, 2005.
Accepted for publication June 24, 2005.

Pulmonary Bioactivation of Trichloroethylene to Chloral Hydrate: Relative Contributions of CYP2E1, CYP2F and CYP2B1

Poh-Gek Forkert 1*, R. Michael Baldwin 2, Brandie Millen 1, Lawrence H. Lash 3, David A Putt 3, Michael A Shultz 2, Kathy S Collins 1

1 Queen's University 2 UC Davis 3 Wayne State University School of Medicine

* Address correspondence to: E-mail: forkertp{at}post.queensu.ca

Abstract

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 (Vmax/Km = 0.79) for generating CH was greater than those of recombinant CYP2F4 (Vmax/Km = 0.27), recombinant mouse CYP2F2 (Vmax/Km = 0.11), recombinant rat CYP2B1 (Vmax/Km = 0.07) or recombinant human CYP2E1 (Vmax/Km = 0.02). Decreases in immunoreactive lung microsomal CYP2E1, CYP2F2 and CYP2B1 were manifested at varying time-points after TCE treatment. The loss of immunoreactive CYP2F2 occurred prior to those 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 lung 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 out of eight subjects. These results showed that, although recombinant 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.


Key words: bioactivation, cytochrome P450 isoforms, inactivation, lung cytochrome P450, microsomes, pneumotoxicity, pulmonary metabolism, pulmonary toxicology


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