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Drug Metabolism and Disposition Fast Forward
First published on June 21, 2006; DOI: 10.1124/dmd.106.010439

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Received for publication April 6, 2006.
Revised June 15, 2006.
Accepted for publication June 16, 2006.

Inhibition of the Human Liver and Human Cytochrome P450 1A2 and 3A4 Metabolism of Estradiol by Deployment-Related and Other Chemicals

Khawja A Usmani 1, Taehyeon M Cho 1, Randy L. Rose 1, Ernest Hodgson 1*

1 North Carolina State University

* Address correspondence to: E-mail: ernest_hodgson{at}ncsu.edu

Abstract

Abstract Cytochrome P450s (CYPs) are major catalysts in metabolism of xenobiotics and endogenous substrates such as estradiol (E2). It has previously been shown that E2 is predominantly metabolized in humans by CYP1A2 and 3A4 with 2-hydroxyestradiol (2-OHE2) the major metabolite. This study examines effects of deployment-related and other chemicals on E2 metabolism by human liver microsomes (HLM) and individual CYP isoforms. Kinetic studies using HLM, CYP3A4, and CYP1A2 demonstrated similar affinities (Km) for E2 with respect to 2-OHE2 production. Vmax and CLint values for HLM are 0.32 nmol/min/mg protein and 7.5 µl/min/ mg protein, those for CYP3A4 are 6.9 nmol/min/nmole CYP and 291 µl/min/ nmol CYP and those for CYP1A2 are 17.4 nmol/min/nmole CYP and 633 µl/min/ nmol CYP. Phenotyped HLM use demonstrated that individuals with high levels of CYP1A2 and CYP3A4 have the greatest potential to metabolize E2. Preincubation of HLM with a variety of chemicals, including those used in military deployments, resulted in varying levels of inhibition of E2 metabolism. The greatest inhibition was observed with organophosphorus compounds, including chlorpyrifos and fonofos, with up to 80% inhibition for 2-OHE2 production. Carbaryl, a carbamate pesticide, and naphthalene, a jet fuel component, inhibited ca. 40% of E2 metabolism. Preincubation of CYP1A2 with chlorpyrifos, fonofos, carbaryl, or naphthalene resulted in 96, 59, 84, and 87% inhibition of E2 metabolism, respectively. Preincubation of CYP3A4 with chlorpyrifos, fonofos, deltamethrin or permethrin resulted in 94, 87, 58 and 37% inhibition of E2 metabolism. Chlorpyrifos inhibition of E2 metabolism is shown to be irreversible.


Key words: CYP inhibition, CYP1A, CYP3A, cytochrome P450, human CYP enzymes, liver microsomes, steroids




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